Randomised Study Comparing the Effects of Inhaled FF/GW642444M Combination, FF and GW642444M 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 FF/GW642444M Combination, FF and GW642444M on an Allergen Induced Asthmatic Response (NCT01128595), a randomized phase 2 study. The primary outcome is Late Asthmatic Response (LAR): Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) Following the 1-hr Post-treatment Allergen Challenge on Day 21 of Each Treatment Period.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, double-blind, placebo-controlled, four-way crossover, repeat-dose study in participants with mild asthma. The registry lists 27 enrolled and records the study as completed. Its stated purpose was to use an inhaled allergen challenge model to explore the individual contributions of a long-acting beta agonist/inhaled corticosteroid combination and its components to protection from allergic triggers in asthma.

The four registered treatment arms were placebo, FF/VI 100/25 µg OD, FF 100 µg OD, and VI 25 µg OD. The official study title describes the combination and component treatments as fluticasone furoate/GW642444M, GW642444M, and fluticasone furoate. The registry record does not report the treatment sequence, washout arrangements, or the duration of each treatment period, beyond identifying repeat dosing and a crossover model. It also does not report arm-specific dosing instructions beyond the treatment labels.

In a crossover design, participants receive more than one treatment, so comparisons can use information from treatment periods within participants. This can account for stable differences between participants, although period effects and other design features still matter. The primary outcome description says the least-squares means were adjusted for period, participant, and period baselines. Further details of the model are not reported in the registry record.

The primary endpoint was assessed on Day 21 of each treatment period, following an allergen challenge administered one hour after dosing. The primary outcome timeframe is Day 21 of each treatment period, up to Study Day 197. A secondary methacholine measure was assessed on Day 22, up to Study Day 198. The registry record does not report how the crossover sequence was generated or the rationale for the planned enrollment.

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: Participants meeting all of the inclusion criteria and none of the exclusion criteria during the Screening Visit, conducted 14-42 days prior to the first dose of study medication, entered a 14-day Run-in Period. Participants were then randomized to 4 Treatment Periods, each lasting 21 days and separated by a nominal washout period of 21-35 days.

Treatment Period 1

Washout Period 1

Treatment Period 2

Washout Period 2

Analysis population for the primary outcome, as defined in the registry: Efficacy Population: all participants who received at least one dose of study medication, had a post-dose FEV1 assessment, and who were not major protocol violators. Only those participants available at the specified time points were analyzed.

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 Late Asthmatic Response (LAR): Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) Following the 1-hr Post-treatment Allergen Challenge on Day 21 of Each Treatment Period, measured over Day 21 of each treatment period (up to Study Day 197).

The primary endpoint was the absolute change from saline in minimum FEV1 during the late asthmatic response. FEV1 is the maximum amount of air that can be forcefully exhaled in one second and is used as a measure of lung function. Participants inhaled an allergen one hour after dosing on Day 21 of each treatment period. Minimum FEV1 was the lowest post-saline FEV1 measurement from 4 through 10 hours after the challenge, including measurements at the stated interval time points. The endpoint was calculated by subtracting the saline FEV1 value from that minimum.

The saline value was defined as the maximum of three single FEV1 measurements recorded after saline inhalation. A negative change therefore indicates that the minimum post-challenge FEV1 was below the saline value; the size and precision of the estimate matter when interpreting the arm results. The registry reports least-squares means, adjusted for period, participant, and period baselines, with 95% confidence intervals.

This endpoint is used to quantify the late lung-function response following a controlled allergen challenge. It provides a continuous measurement, rather than a simple event count, and captures the minimum FEV1 across a defined post-challenge window. It does not by itself describe every aspect of asthma, everyday symptoms, or longer-term outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous and is reported in liters as a least-squares mean change from saline. A mean describes the central value of a set of measurements. A least-squares mean is a model-based estimate that accounts for factors included in the analysis; the registry says these estimates were adjusted for period, participant, and period baselines. This matters in a crossover study because the same participant can contribute information under more than one treatment, and measurements may also differ by treatment period.

What does a confidence interval say?

A 95% confidence interval expresses the uncertainty in an estimated quantity under the analysis method. A narrower interval indicates greater precision than a wider interval, but neither interval describes the full range of individual participant responses. For the primary outcome, each arm estimate has a 95% confidence interval, and each reported contrast has its own 95% confidence interval. A contrast interval that includes zero is compatible with no difference in the direction represented by that contrast under the analysis; an interval that excludes zero does not by itself establish clinical importance or resolve multiplicity.

The registry reports the primary arm estimates and five contrasts but no p-values for those contrasts. Their values and confidence intervals are sponsor-reported results. No alternative recalculation of the primary endpoint is included in the posted secondary calculations, so the sponsor’s primary estimates and comparisons are the relevant reported analysis.

How should the secondary continuous outcome be read?

The posted methacholine outcome is PC20, the provocative concentration estimated to result in a 20% reduction in FEV1. It is reported as a mean with a standard deviation, in milligrams per milliliter. A standard deviation describes the spread of observations around the mean; it is not a confidence interval for the mean. The registry reports arm means and standard deviations, while the pairwise contrasts and related calculations are unadjusted recalculations from posted summary statistics. They are not the sponsor’s reported analyses, and the registry has no reported analysis for this endpoint.

For the recalculated PC20 comparisons, the mean difference is the difference between the posted arm means, and the confidence interval describes uncertainty under the recalculation method. The unadjusted p-values do not account for multiple comparisons. The pooled standard deviation is used in the standardized effect and planning illustration; it is a measure of variation combining information from the two compared arms. When observations are highly variable relative to the mean, a mean difference may be estimated with limited precision. That is a general statistical consideration, not evidence about the shape of the PC20 distribution in this study.

What do the planning figures represent?

The sample-size planning illustration uses the observed recalculated effect, or a stated fraction of it, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The resulting figures are planning examples for participants per arm for 80% power or 90% power under those assumptions. They are not the trial’s original design calculation, not evidence of the trial’s observed power, and not a guarantee that a future study would achieve the stated power. The registry record does not report the trial’s own sample-size justification or assumptions.

These planning illustrations are sensitive to the effect size and variability used. Using a smaller fraction of the observed effect requires a larger planned sample under otherwise unchanged assumptions. The estimates are based on the posted summary statistics, rather than participant-level data or a full crossover model, and therefore do not replicate the design of this trial. In particular, the illustration assumes equal allocation between two arms; the registry describes a four-way crossover study and does not report a planning method that matches that design.

More generally, a statistical model depends on how outcomes are distributed, how observations relate to each other, and how missing measurements are handled. The registry describes adjustment for period and participant for the primary least-squares means but does not report the full model specification, covariance structure, or diagnostics. A crossover analysis must address the dependence of repeated measurements within participants; general methods that treat every treatment-period measurement as independent could misstate uncertainty. The registry record does not give enough detail to determine precisely how those issues were handled beyond the reported adjustment.

10. Analyses Reported by the Sponsor

The primary endpoint results are reported as least-squares means and pairwise mean differences, with 95% confidence intervals. Those are the sponsor-reported analyses in the registry record. The comparisons have no reported p-values, and the registry does not state whether or how multiplicity was addressed. They should therefore be read as the posted estimates and intervals, with their uncertainty, rather than as a complete account of all inferential decisions.

The methacholine PC20 outcome has no sponsor-reported pairwise analyses in the registry record. The displayed comparisons and unadjusted p-values for that outcome are recalculations from the posted arm summary statistics. They use a simpler, unadjusted approach and do not reproduce a reported sponsor model. The confidence intervals and p-values from those calculations may therefore differ from results that a participant-level or crossover-adjusted analysis would produce.

No discrepancy is flagged between a recalculation and a sponsor analysis in the registry record. Where a discrepancy is flagged, the sponsor’s own analysis takes precedence over a simple recalculation. For the primary endpoint, no recalculated comparison is offered in place of the sponsor’s reported contrasts. The PC20 planning figures are illustrations based on the recalculated effect and stated assumptions; they are not the trial’s original design calculations or observed power.

For careful interpretation, distinguish the primary sponsor-reported outcome from the secondary unadjusted calculations. Both describe posted data, but their analytical status is different. The registry record does not report additional modeling details that would allow independent reproduction of the sponsor’s primary analysis.

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint has four treatment arms and five reported pairwise contrasts. The registry record does not report a multiplicity adjustment, a prespecified hierarchy among the comparisons, or a rule for deciding which comparisons were primary for inference. Without that information, the confidence intervals should be read as reported for each individual contrast, not as a family of intervals adjusted to maintain a particular overall error rate. The absence of reported p-values for the primary contrasts also means those values cannot be used to infer an unreported testing strategy.

The secondary outcomes add further comparisons. The PC20 p-values are unadjusted recalculations, so they do not account for the number of endpoints or contrasts considered. The record does not report a multiplicity plan for the secondary outcomes. The maximum percent change from saline in FEV1 is identified as a secondary outcome, but its results are not reported in the registry record. The registry also does not report whether interim analyses were planned or conducted.

For the primary efficacy analysis, the population is described as participants who received at least one dose, had a post-dose FEV1 assessment, and were not major protocol violators. Only those available at the specified time points were analyzed. The number analyzed varies across the primary treatment arms. The record does not report how missing measurements were imputed, whether sensitivity analyses were performed, or the reasons observations were unavailable. It therefore does not establish whether missingness was related to treatment or outcome.

The primary least-squares means were adjusted for period, participant, and period baselines. The registry does not provide the full statistical model, assumptions about within-participant correlation, or details of any protocol deviations beyond the population definition. Sequence effects, carryover handling, and the method used to account for incomplete treatment periods are not reported in the registry record. These omissions limit independent assessment of the crossover analysis and its robustness. The reported estimates remain interpretable as the registry’s posted results, but the record does not support a complete reconstruction of the analysis plan.

12. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures report zero affected participants in each listed treatment group. The corresponding at-risk counts are 27 for placebo, 27 for FF/VI 100/25 µg OD, 27 for FF 100 µg OD, and 26 for VI 25 µg OD. No serious adverse event terms are listed. Death counts are not reported in the registry record.

These figures are counts of participants with at least one serious adverse event, not a full description of all adverse events or their timing, severity, or relationship to treatment. The registry also reports other adverse events in each group, but the serious-event counts alone do not describe that broader safety information. In a crossover trial, treatment-group safety counts may reflect exposure across treatment periods; the registry record does not explain the counting rules or provide detailed exposure time.

A zero count in these groups means no affected participants were recorded for this measure in the posted results. It does not establish that serious events are impossible, nor does it quantify the safety profile beyond the observed trial record. The study’s enrollment and follow-up provide a limited basis for assessing uncommon events, and the registry does not report enough detail to assess risk by event type or duration.

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

The posted primary results describe changes in minimum FEV1 from a saline reference after an inhaled allergen challenge. They show negative average changes in every treatment arm, with different estimated magnitudes and uncertainty intervals. The sponsor-reported contrasts quantify selected differences among the arms. These are results for a defined challenge response and measurement window, not a complete assessment of asthma control or every outcome that may matter to participants.

The estimates do not by themselves establish how meaningful a difference is in clinical practice. The registry record does not report a threshold for clinical importance, and the study’s controlled allergen challenge is not the same as measuring long-term outcomes in routine settings. The record also does not report outcomes such as symptoms, exacerbations, or quality of life as part of the posted results. No conclusion about those unreported outcomes follows from the FEV1 estimates.

The confidence intervals communicate statistical uncertainty, but they do not eliminate uncertainty about the design, analysis, missing observations, or generalizability. The crossover structure permits within-participant comparisons, and the reported model adjusts for period and participant, but important modeling details are not reported. The analyzed counts also differ between arms, and only participants available at specified time points were analyzed.

The secondary PC20 calculations are unadjusted and should be treated as exploratory context. They do not substitute for the primary sponsor analysis, and the maximum percent change secondary outcome has no posted results in the registry record. Neither the primary nor secondary findings establish effects in people outside the study population or beyond the study’s challenge setting. The most defensible reading is limited to the measured outcomes, the reported comparisons, and their stated uncertainty.

14. Why This Trial Matters Statistically

This trial is statistically notable because it compares a combination treatment with its components in a randomized four-way crossover design. The design is intended to examine how the individual treatment arms relate to the response under a controlled allergen challenge. Repeated treatment periods can make within-participant contrasts informative, while requiring an analysis that accounts for participant-level dependence and period effects.

The registry reports least-squares means adjusted for period, participant, and period baselines, making those features central to understanding the primary estimates. It also reports arm-specific confidence intervals and several treatment contrasts. The intervals make clear that point estimates should not be read without their precision, and that comparisons can have different levels of uncertainty even within one outcome.

The record is also a useful example of why the analysis status of a result matters. The primary contrasts are sponsor-reported, whereas the PC20 comparisons and planning illustrations are recalculations from summary statistics. These are not interchangeable evidence. The secondary calculations use an unadjusted approach and do not reproduce a reported crossover model. Planning estimates are hypothetical design aids, not evidence about the power achieved in this completed study.

Finally, the registry’s incomplete reporting of multiplicity, missing-data handling, and model details constrains how fully the findings can be evaluated. The posted results can still be described precisely, but statistical interpretation should distinguish what was estimated from what remains undocumented. That distinction is especially important in a trial with several arms, outcomes, and pairwise comparisons.

15. Limitations

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

The registry record does not report the planned sample-size justification, treatment sequence, washout arrangements, or full crossover analysis model. It identifies adjustment for period, participant, and period baselines for the primary least-squares means, but does not describe the model’s covariance structure, carryover handling, or sequence effects. These details matter when interpreting repeated treatment-period measurements.

Primary efficacy analyses included only participants available at the specified time points, and the arm-specific analyzed counts differ. The record does not report reasons for missing measurements, imputation methods, or sensitivity analyses. It therefore leaves uncertainty about how incomplete observations may have affected the estimates. The registry also does not report a multiplicity procedure for the primary contrasts or secondary outcomes.

The sponsor reports primary contrasts without p-values. The secondary PC20 comparisons are unadjusted recalculations from arm summaries rather than sponsor-reported analyses, and the maximum percent change secondary outcome is identified without posted results. The PC20 planning illustration uses a two-arm normal approximation and equal allocation, which is not a reproduction of this four-way crossover design or the trial’s original planning. It should be treated only as an illustration.

The study uses a controlled inhaled allergen challenge and a specific lung-function endpoint in participants with mild asthma. The registry record does not establish how directly these results apply to other populations, settings, or outcomes. The safety record also gives limited event detail: serious adverse event counts are reported, but death counts and fuller descriptions of event timing and treatment exposure are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Randomised Study Comparing the Effects of Inhaled FF/GW642444M Combination, FF and GW642444M on an Allergen Induced Asthmatic Response — NCT01128595.
• Registry record last updated 2017-01-18; status last verified 2016-11.
• Results first posted 2013-08-09.
• 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.

19. Record Summary

NCT01128595 is a completed Phase 2 randomized, double-blind, placebo-controlled, four-way crossover, repeat-dose study in participants with mild asthma. The registry lists 27 enrolled and describes comparisons of FF/VI 100/25 µg OD, FF 100 µg OD, VI 25 µg OD, and placebo using an inhaled allergen challenge.

The primary endpoint was absolute change from saline in minimum FEV1 during the 4–10-hour late asthmatic response window after challenge on Day 21 of each treatment period. The record reports least-squares means and pairwise contrasts with 95% confidence intervals. It also posts PC20 summaries and unadjusted recalculations, while results for the identified maximum percent change secondary outcome are not reported in the registry record.

Interpretation is limited by unreported details on multiplicity, missing-data handling, and the full crossover model. The primary results are sponsor-reported; secondary recalculations and sample-size planning illustrations are not the trial’s own analyses or design justification.