Efficacy, Safety, Tolerability, and Pharmacokinetics of Indacaterol Salts in Patients With Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy, Safety, Tolerability, and Pharmacokinetics of Indacaterol Salts in Patients With Asthma (NCT00927901), a randomized phase 2 study. The primary outcome is Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7).

2. Clinical Question

The central statistical feature is that the trial studied several salt formulations in the same crossover framework. A crossover design can support within-participant comparisons because participants receive treatments in different periods. That makes interpretation dependent not only on the arm-level estimates but also on the analysis used to account for the crossover structure. The registry describes an adjustment for period baseline FEV1, but further details of the primary statistical model are not reported in the registry record.

The study also included secondary questions about early FEV1 response, rescue-medication use, and pharmacokinetic exposure. Those measures broaden the description of the treatment periods, but the registry record does not post results for every listed secondary outcome. The primary question should therefore be read narrowly: it concerns the reported Day 7 trough FEV1 changes, not every measure named in the trial objectives.

3. Trial Design

This was a Phase 2, randomized, quadruple-masked, placebo-controlled, 4-way crossover study. Its official title describes a multi-centre, multiple-dose study of orally inhaled indacaterol maleate, xinafoate, and acetate in patients with persistent asthma. Enrollment was 30. The registry lists the study as completed, with a start in 2009-06 and primary completion in 2009-11.

In a crossover trial, participants pass through treatment periods rather than remaining in a single parallel treatment group throughout. The registry describes four sequences that place the three indacaterol salts and placebo in different orders. This structure means that each participant can contribute observations under more than one treatment condition, while treatment order and period are relevant to interpretation. The registry does not report the duration of any washout, if one was used, or further details about the sequence-generation process.

Randomization and quadruple masking are listed, but the record does not specify which roles were masked or how masking was maintained. Allocation concealment procedures and the randomization method are not reported in the registry record. The overall design and sequence descriptions identify the intended treatment structure, but they do not supply all operational details needed to reconstruct the trial conduct.

The primary outcome was change from baseline in trough FEV1 24 hours after dosing at the end of each treatment period, on Day 7. The primary endpoint population was restricted to randomized subjects who received at least 1 dose and had baseline and post-baseline FEV1 measurements. The reported endpoint denominators were 28 for maleate, 29 for acetate, 28 for xinafoate, and 29 for placebo. These are the posted endpoint counts; the registry does not explain the differences between those counts and the enrollment total.

The record lists five secondary outcomes in addition to the primary endpoint. These include Day 1 trough FEV1, time to peak FEV1 on Day 1 and Day 7, rescue-medication use, and pharmacokinetic exposure measures. Results are posted for rescue-medication use, but the other named secondary results are not reported in the registry record.

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.

Treatment Period 1

Reasons for not completing this period:

Treatment Period 2

Treatment Period 3

Treatment Period 4

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy analysis set: All randomized subjects that received at least 1 dose of study drug and had a baseline and at least 1 post-baseline measurement of FEV1.

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 Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7), measured over Baseline to the end of each treatment period (Day 7).

The primary endpoint was change from baseline in trough forced expiratory volume in 1 second (FEV1), measured 24 hours after dosing at the end of each treatment period on Day 7. FEV1 is the volume of air exhaled in the first second of a forced breath. The endpoint therefore describes a lung-function measurement at a specified time after dosing, rather than an average across the entire treatment period.

The registry defines trough FEV1 as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes after dosing, at baseline and at the end of each period. Spirometry was conducted according to internationally accepted standards. The primary result is expressed in liters, with a positive change indicating an increase from the baseline value and a negative change indicating a decrease.

Using a change from baseline focuses the result on movement from each participant's starting measurement. Measuring at the end of each treatment period gives a repeated-period endpoint aligned with the crossover design. The registry's description also states that period baseline FEV1 was included as a covariate. As a general statistical principle, adjustment for a baseline value can account for variation in starting measurements and may improve precision; the registry does not report enough model detail to assess the exact implementation.

The endpoint is a physiological measure. It does not, by itself, summarize symptoms, daily functioning, rescue-medication use, or all aspects of safety. Those are separate questions, and the registry lists some as secondary outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports least-squares mean changes and 90% confidence intervals for the primary endpoint. A least-squares mean is a model-based average, adjusted for covariates included in the analysis. The registry explicitly identifies period baseline FEV1 as a covariate. It does not give the complete model formula, list all modeled effects, describe assumptions about within-participant correlation, or explain how missing measurements were handled.

What does a confidence interval communicate?

As a general statistical explanation, a confidence interval describes uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, but an interval is not a guarantee that the true value lies within its limits. The registry chose 90% confidence intervals for this outcome. The endpoints are posted to four decimal places, which exceeds the limit for numerical precision in this explanation, so the arm estimates can be described without repeating those interval limits.

For the active formulations, the posted intervals do not include zero; the placebo interval includes zero. This is a description of each change estimate relative to zero change. It is not a direct test of an active formulation against placebo. In a crossover study, the scientifically relevant treatment contrast is ordinarily based on comparisons within participants, with suitable accounting for period and other design features. No primary treatment-contrast estimates are posted in the registry record.

Why does the crossover structure matter?

As a general principle, crossover data contain repeated observations from the same participants. Measurements from one participant are usually related to one another, so an analysis needs to respect that dependence rather than treating every treatment-period observation as if it came from an unrelated person. Crossover analyses may also need to account for period and treatment sequence. The registry identifies period baseline FEV1 as a covariate but does not report the rest of the model or how it handled within-participant correlation, sequence, or possible carryover. Those elements are not reported in the registry record and should not be assumed.

The posted least-squares means summarize adjusted changes by treatment condition. Without the estimated contrasts and their uncertainty, readers cannot recover the crossover comparison from those means alone. A direct contrast requires information about the relation between the repeated measurements, not just the separate arm means and confidence intervals.

How should the rescue-medication comparisons be read?

The registry gives percentages and counts for rescue-medication use during the treatment periods. Two unadjusted recalculated comparisons are listed: maleate versus placebo has p = 1.0, and acetate versus placebo has p = 0.254. These recalculations compare the posted summary counts without adjustment for other factors or for the trial's crossover structure. The record does not list reported sponsor analyses for this outcome, and a comparison for xinafoate is not posted.

A p-value is a measure of how incompatible the observed data are with a specified null model, under the assumptions used for the calculation. It is not the probability that a treatment effect is true, and it does not measure the size or clinical importance of an effect. Because these recalculated comparisons are unadjusted and the method does not reflect all details of the crossover design, they warrant less weight than a prespecified analysis that uses participant-level data and accounts for the design.

What do the sample-size illustrations mean?

The registry includes planning illustrations based on the observed rescue-medication effect for acetate versus placebo, rather than on the trial's original design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrations consider planning for 100%, 75%, and 50% of the observed effect. For 80% power, the listed participants per arm are 178, 339, and 811, respectively; for 90% power, the listed participants per arm are 237, 453, and 1,085, respectively.

As a general statistical principle, planning for a smaller effect requires more participants to achieve the same target power, all else equal. These values are planning illustrations, not estimates of the power achieved in this trial and not evidence that the original trial was designed around these assumptions. The registry does not report the trial's own sample-size justification.

The record does not report a multiplicity procedure, an interim-analysis plan, or a complete statistical analysis plan. Those omissions matter because the study includes several outcomes and treatment comparisons, and the interpretation of nominal results can depend on whether multiple testing was anticipated and addressed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and five secondary outcomes. Across the study, the named measures cover lung function at different times, time to peak FEV1, rescue-medication use, and pharmacokinetic exposure. Testing several outcomes or multiple treatment contrasts raises a multiplicity question: as a general statistical principle, the chance of at least one apparently unusual result can increase when many hypotheses are examined. The registry does not report whether any adjustment, hierarchy, or other multiplicity strategy was planned.

The registry reports no listed analyses for the posted outcomes. It gives arm-level primary estimates and secondary rescue-medication summaries, but no complete primary comparison analysis. For the rescue-medication results, the comparison statistics described in the statistical interpretation are unadjusted recalculations, rather than analyses reported by the sponsor. A full statistical analysis plan, including planned contrasts and decision rules, is not reported in the registry record. Interim analyses are also not reported in the registry record.

The primary analysis population is defined as all randomized subjects who received at least 1 dose of study drug and had baseline and at least 1 post-baseline FEV1 measurement. That definition clarifies which participants could contribute to the primary efficacy analysis. It is not an intention-to-treat definition covering every randomized participant regardless of treatment receipt and measurement availability. The registry does not report the number excluded from the efficacy set or the reasons for any exclusions.

Primary endpoint counts vary by treatment condition, and the rescue-medication counts also differ by condition. The registry does not explain the missingness or provide a missing-data method, imputation strategy, or sensitivity analysis. It is therefore not possible to determine from the record whether missing observations were related to treatment, period, or participant characteristics. The analysis's robustness to missing data is not reported in the registry record.

The primary description includes adjustment for period baseline FEV1, but other details needed to assess model adequacy are absent. In particular, treatment and period terms, within-participant covariance assumptions, sequence effects, and handling of carryover are not described. These omissions do not prove that such procedures were absent from the study; they mean only that they are not reported in the registry record.

11. 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 non-serious adverse event terms

The registry reports zero serious adverse events for each treatment condition. The listed numbers at risk were 30 for indacaterol acetate, 29 for indacaterol maleate, 29 for indacaterol xinafoate, and 29 for placebo. These figures describe the posted serious-event counts in the registry, not a guarantee that the study can exclude uncommon harms or characterize safety beyond its observed participants and treatment periods.

In a crossover study, participants may contribute safety information under more than one condition. The treatment-specific numbers at risk should therefore be read as period-level exposure counts rather than added as if they were mutually exclusive groups of different people. The registry does not post serious adverse-event terms, and death counts are not reported in the registry record.

The record also lists other, non-serious adverse-event counts, but those are distinct from serious adverse events. Serious-event figures alone do not capture all tolerability information, and the limited size and duration of the study restrict the scope of safety conclusions that can be drawn from these counts.

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

The posted primary results describe changes in trough FEV1 during the treatment periods. The least-squares mean changes are positive for the three indacaterol salts and negative for placebo. The reported confidence intervals characterize uncertainty around those arm-specific estimates. These results are descriptive summaries of the endpoint as recorded; they are not, on their own, a formal demonstration of how much one treatment differs from another.

The distinction between within-condition change and between-treatment difference is important. Each arm estimate describes change from baseline under that treatment condition. A treatment comparison asks whether the change under one condition differs from the change under another. In a crossover trial, this comparison should use the repeated measurements from the same participants and account for the study design. The registry does not report the primary contrasts needed to quantify that difference.

Nor does a physiological endpoint alone answer every question about treatment experience. The registry lists secondary measures of rescue-medication use, time to peak FEV1, and pharmacokinetic exposure, but reports only partial secondary results. Their absence from the record means those questions remain unresolved in the posted information; it does not establish that the outcomes were not measured.

Zero serious adverse events are reported in the treatment conditions, but that observation should be interpreted in the context of the small enrollment and the treatment-period counts. It cannot establish that serious events are impossible, nor does it replace a broader evaluation of adverse events or longer-term safety. Death counts are not reported in the registry record.

Overall, the registry supports a narrow account of the study: a short, randomized crossover evaluation with arm-level primary FEV1 estimates and limited secondary and safety summaries. It does not report enough statistical detail or direct primary comparisons to support a complete assessment of relative treatment effects. No clinical recommendation follows from these registry summaries alone.

13. Why This Trial Matters Statistically

This trial illustrates why the design and the reported estimand matter as much as the displayed averages. In a crossover study, repeated treatment conditions within participants can make paired comparisons informative. But arm-specific means do not reveal the size or precision of those paired contrasts. A reader needs direct comparison estimates and a model that respects the repeated-measure structure to judge the relative effects.

The registry does provide a useful starting point: it identifies the primary endpoint, defines the efficacy analysis population, reports the period-baseline covariate, and gives arm-level changes with confidence intervals. Those details help distinguish an adjusted estimate from a raw average and clarify that the primary measure is a Day 7 trough value rather than a general measure across the treatment period.

The limits are equally instructive. The record does not report the primary contrast results, full analysis model, missing-data approach, multiplicity procedure, or the trial's sample-size justification. The planning illustrations are based on an observed secondary effect and are not evidence about the study's achieved power. Treating them as such would confuse prospective planning with retrospective inference.

The trial also makes the distinction between measurement domains visible. FEV1, rescue-medication use, pharmacokinetic exposure, and adverse events answer different questions. One cannot be substituted for another, and incomplete secondary reporting leaves gaps even when the primary endpoint is available. Statistically, a responsible reading keeps each result tied to its endpoint, analysis, and uncertainty, while resisting conclusions that the registry's reported estimates cannot support.

14. 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 most important trial-specific limitation in the registry record is the lack of direct primary comparisons. The results give least-squares mean changes for each treatment condition, but do not report treatment-minus-placebo or between-salt estimates with uncertainty. In a crossover design, those contrasts are central to interpreting relative effects; separate arm confidence intervals are not a substitute.

The endpoint is a short-period physiological measurement at the end of Day 7. The record also names outcomes that could contribute different information, but it does not report results for several of them, including Day 1 trough FEV1, time to peak FEV1, and pharmacokinetic exposure. This limits the breadth of the registry-based interpretation.

The total enrollment was 30, and the primary endpoint counts range from 28 to 29 across treatment conditions. The record does not explain the denominator differences or report missing-data handling. It also does not give the complete analysis model, including how within-participant dependence, treatment period, sequence, or possible carryover were addressed. These are reporting limitations; the record does not establish that the underlying study lacked such methods.

Further limitations include the absence of a reported multiplicity strategy, interim-analysis details, and the trial's own sample-size justification. The rescue-medication comparisons available in the registry are unadjusted recalculations, and not every treatment contrast is present. The sample-size illustrations are based on the observed effect for one secondary comparison and should not be used to infer the trial's original design or achieved power.

Finally, the serious-event counts describe a limited set of participants and periods. Death counts are not reported in the registry record, and serious-event counts alone do not provide a complete account of safety or tolerability.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy, Safety, Tolerability, and Pharmacokinetics of Indacaterol Salts in Patients With Asthma — NCT00927901.
• Registry record last updated 2013-09-09; status last verified 2013-08.
• Results first posted 2011-08-30.
• 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.

18. Record Summary

NCT00927901 is a completed Phase 2 randomized, quadruple-masked, placebo-controlled, 4-way crossover study of three orally inhaled indacaterol salts in patients with persistent asthma. Enrollment was 30. The primary outcome was change from baseline in trough FEV1 at the end of each treatment period on Day 7, reported as least-squares means with 90% confidence intervals.

The registry posts arm-specific primary estimates but no primary between-treatment comparisons. It reports rescue-medication summaries and limited unadjusted recalculated comparisons, while results for several named secondary outcomes are not reported in the registry record. Serious adverse-event counts are zero in each treatment condition; death counts are not reported in the registry record. Important analysis details, including multiplicity and missing-data methods, are also not reported.