Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Two Orally Inhaled Indacaterol Salts in Adult Subjects With Asthma.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Two Orally Inhaled Indacaterol Salts in Adult Subjects With Asthma. (NCT03257995), a randomized phase 2 study. The primary outcome is Trough FEV1.

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, placebo-controlled, three-period crossover study in patients with asthma. The registry record lists phase 2, quadruple masking, and an enrollment of 54. The study is marked completed. The listed start date is 2017-09-05, and the primary completion date is 2018-01-17.

Participants were assigned to one of six treatment sequences, represented as A-B-C, B-C-A, C-A-B, A-C-B, B-A-C, and C-B-A. The registry record does not identify the treatment represented by each letter, so the sequence labels alone do not establish the order of the named treatments. In a crossover design, treatment effects can be compared using observations collected from the same participants across periods. That structure can account for stable differences between participants, but interpretation can also depend on period, sequence, and carryover considerations. The registry record does not report the protocol details for handling those considerations.

The primary measurement was trough FEV1 on Day 14 of each treatment period. The primary pharmacodynamic analysis set included participants with available pharmacodynamic parameter data who received any study drug and experienced no major protocol deviations with relevant impact on those data. The posted group summaries contain different numbers of participants by treatment: 51 for maleate, 52 for acetate, and 53 for placebo. The registry record does not explain the difference between these analysis counts and the enrolled total, or provide a participant-flow account.

The trial included pharmacokinetic and additional FEV1 outcomes as secondary measures. Across these measures, the registry record lists 16 outcome measures and indicates that 15 secondary outcomes were posted. The protocol’s original sample-size justification, allocation details beyond the listed sequence assignments, and full analysis plan 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data

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 Trough FEV1, measured over Day 14 of each of the three treatment periods.

The primary endpoint was trough FEV1, measured in liters on Day 14 of each of the three treatment periods. FEV1 is the amount of air a person can forcibly exhale from the lungs during the first second of a forced exhalation. A trough measurement captures lung function at the specified low point in the dosing interval; the registry record identifies the timing as Day 14 but does not give further operational details about the exact measurement schedule.

FEV1 is a continuous measure, so the registry record reports means and standard deviations for each treatment group. Treatment differences are expressed as mean differences. A difference in means gives the estimated separation between treatment conditions in the measured outcome, while a confidence interval describes the range of values reasonably compatible with the analysis and its assumptions.

Using trough FEV1 as the primary endpoint allowed the study to compare the two indacaterol salts with placebo after repeated treatment, and to compare the salts with one another. The endpoint therefore addresses lung function at a specified treatment time rather than only the change immediately after a dose. The primary description defines the three contrasts but does not report a clinically important difference threshold. It also does not report the original rationale for choosing this endpoint or how the endpoint was incorporated into the trial’s design calculations.

7. Results Posted in the Registry

• Indacaterol Maleate: mean 2.42 versus 2.22 on control; difference 0.20 (95% CI -0.09 to 0.49), standardized effect d = 0.26; z-test p = 0.180.
• Indacaterol Acetate: mean 2.38 versus 2.22 on control; difference 0.16 (95% CI -0.13 to 0.45), standardized effect d = 0.21; z-test p = 0.280.

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.

Pharmacokinetics AUC 0-24hours at Steady State

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Indacaterol Acetate 150 µg: mean 2,050 versus 2,300 on control; difference -250.00 (95% CI -515.03 to 15.03), standardized effect d = -0.36; z-test p = 0.064.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Indacaterol Acetate 150 µg and the control. The interval gives the range of effects that remain compatible with the data.

Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Indacaterol Acetate 150 µg: mean 0.91 versus 0.91 on control; difference -0.00 (95% CI -0.09 to 0.09), standardized effect d = -0.01; z-test p = 0.966.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Indacaterol Acetate 150 µg and the control. The interval gives the range of effects that remain compatible with the data.

Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC.

• 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:
  • Indacaterol Maleate 150 µg: mean 2.52 versus 2.27 on control; difference 0.25 (95% CI -0.06 to 0.56), standardized effect d = 0.31; z-test p = 0.118.
  • Indacaterol Acetate 150 µg: mean 2.52 versus 2.27 on control; difference 0.24 (95% CI -0.07 to 0.56), standardized effect d = 0.30; z-test p = 0.123.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Indacaterol Maleate 150 µg and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Indacaterol Acetate 150 µg and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover pharmacokinetic measures, relative bioavailability, and additional lung-function summaries. Together, these outcomes describe exposure to the salts and lung-function measurements at other specified times or using different summaries from the primary trough measure. Their varied definitions mean they do not all answer the same question, and agreement across them would be informative without making them interchangeable with the primary endpoint.

At a broad level, the posted results include comparisons of drug exposure between the salts and lung-function summaries comparing each salt with placebo. Some secondary analyses show estimates with uncertainty that includes no difference in the simple recalculations, while the sponsor-reported analyses for the posted standardized FEV1 AUC comparisons report p < 0.001. The bioavailability and exposure measures add pharmacokinetic context rather than directly replacing the primary trough FEV1 result. This pattern should be interpreted in light of the specific analysis used and the discrepancy between the sponsor analyses and summary-based recalculations.

The registry record lists 16 outcome measures and 15 posted secondary outcomes. When many outcomes and contrasts are considered, the possibility of chance findings across the collection increases unless a plan controls or prioritizes those tests. The registry record does not report a multiplicity adjustment or a confirmatory hierarchy for the secondary outcomes. Their results therefore carry less weight than a prespecified primary analysis and are best treated as supportive, particularly when interpretation depends on an unadjusted comparison.

These secondary findings do not establish an overall conclusion beyond what the endpoint-specific analyses support. Different measurement times, scales, and statistical summaries can yield different patterns. The registry record does not provide a unified analysis that combines all secondary outcomes, nor does it report a single prespecified criterion for consistency across them. Their role is to add context to the primary result, not to overturn or independently confirm it.

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

• Pharmacokinetics AUC 0-24hours at Steady State
• The Maximum Concentration (Cmax) at Steady State (ss)
• Time of Maximal Plasma Concentration (Tmax) at Steady State
• The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State
• Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate
• Time to Peak FEV1 on Day 14
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints
• Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, and the registry record describes it using means and standard deviations. A mean is the arithmetic average of the measurements in a group. A standard deviation describes how dispersed individual observations are around that group’s mean. Neither measure alone conveys the uncertainty in a treatment contrast; that uncertainty is reflected in a confidence interval and, in a hypothesis test, a p-value.

What does a crossover design change?

In a parallel-group trial, participants generally remain in one assigned treatment group. In a crossover trial, participants receive more than one treatment across separate periods. A comparison can therefore use within-participant information: a participant’s outcome under one treatment can be compared with that same participant’s outcome under another. This can reduce the influence of stable differences between participants. It also means that the analysis may need to account for period and sequence, and for the possibility that effects from an earlier period persist into a later one. Those are general considerations for crossover analyses. The registry record reports ANOVA for the sponsor’s primary comparisons but does not describe the model terms, the handling of period or sequence, or any carryover assessment.

Why do the recalculated and sponsor estimates differ?

The recalculated comparisons use simple, unadjusted calculations from posted group summary statistics. They are not a reconstruction of the sponsor’s crossover model. The sponsor’s reported mean differences and confidence intervals come from ANOVA analyses of final values. A crossover analysis can use information about how the same participants respond across treatments, whereas separate group summaries do not preserve all those participant-level pairings. The record does not report enough model detail or participant-level data to determine exactly why the estimates and intervals differ. Since the discrepancy is flagged, interpretation should give priority to the sponsor’s own analysis.

A p-value measures how compatible the observed data are with a specified null hypothesis under the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The sponsor reported p < 0.001 for each salt-versus-placebo primary contrast. The simple recalculations have unadjusted p-values of 0.18 and 0.28 for those contrasts. These are different analyses, so their p-values are not interchangeable.

What does a confidence interval contribute?

A confidence interval conveys uncertainty around an estimated contrast. A narrow interval indicates more precise estimation under the model; a wide interval indicates greater uncertainty. Whether an interval includes zero is relevant to whether it is compatible with no difference under the corresponding analysis, but it does not tell the reader whether the values in the interval are clinically meaningful. The sponsor’s intervals and the recalculated intervals differ substantially, so the analysis used matters to the interpretation.

For continuous outcomes, assumptions about the data and analysis can affect estimates and uncertainty. General examples include how outcomes are distributed, whether repeated measurements are modeled appropriately, and whether missing observations or protocol deviations alter the analysis population. The registry record describes the primary population and sponsor method at a broad level, but does not report residual diagnostics, transformations, covariance assumptions, missing-data procedures, or sensitivity analyses. These cannot be inferred from the posted summaries.

How should secondary analyses be treated?

The trial reports several pharmacokinetic and lung-function outcomes. Each addresses a different aspect of exposure or response, and some outcomes are measured at different times or summarized differently. Looking across many outcomes creates a multiplicity issue: the chance of finding at least one apparently notable result can rise when many hypotheses are tested. This is a general statistical concern, not evidence that any particular finding is false. The registry record does not report a multiplicity adjustment or a prespecified hierarchy for secondary comparisons. Accordingly, secondary analyses are best read as supportive or exploratory unless the record establishes a stronger confirmatory plan.

The primary analysis population excludes participants with major protocol deviations judged relevant to pharmacodynamic data, according to the registry description. That definition may be appropriate for a specific analysis, but the record does not report how many participants were excluded for each reason, the handling of missing endpoint measurements, or results in another analysis population. The group counts in the posted summaries should therefore be read as the analyzed counts for those summaries, not as a complete account of participant disposition.

11. Confidence Intervals and Precision

The sponsor-reported primary comparisons have 95% confidence intervals that are above zero for maleate versus placebo and acetate versus placebo. Their reported estimates are 0.186 liters and 0.146 liters, respectively. The corresponding intervals are 0.129 to 0.243 liters and 0.090 to 0.203 liters. For maleate versus acetate, the reported estimate is -0.040 liters, with an interval from -0.094 to 0.015 liters. A p-value is not reported for that contrast.

The simple recalculated intervals are much wider. The interval for maleate versus placebo ranges from -0.092 to 0.488 liters, while the interval for acetate versus placebo ranges from -0.129 to 0.446 liters. Both include zero. These intervals reflect simple unadjusted calculations from group summaries; they do not capture the sponsor’s reported crossover analysis. Because the registry record flags a discrepancy, the sponsor’s own analysis takes precedence.

Precision concerns how tightly an analysis estimates a treatment difference, rather than whether an estimate is important. A confidence interval gives a range of values compatible with the data and analysis assumptions. It does not assign equal plausibility to every value in the range, and it does not represent the range of outcomes expected for individual participants. The sponsor’s intervals are more concentrated than the recalculated intervals, but the record does not include sufficient model details to independently assess or reproduce that precision.

The registry record does not report a threshold for a clinically important change in trough FEV1. Consequently, the intervals can describe statistical uncertainty but cannot by themselves determine whether the estimated differences are meaningful in clinical practice. The sponsor-reported results and the summary-based recalculations should remain distinct because they arise from different analytical approaches.

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 participants, for these continuous-outcome illustrations. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as the stated fraction of the observed effect. These are planning illustrations derived from the observed effect, not the trial’s original design justification; the original sample-size assumptions are not reported in the registry record.

The 80% power column indicates the number of participants per arm that the illustration estimates would be needed to have an 80% chance of detecting the selected effect under its assumptions, if that effect were the true one. The 90% power column gives the corresponding planning target for a 90% chance. Higher target power generally requires a larger planned sample, all else equal. The rows using 75% or 50% of the observed effect illustrate planning for smaller effects than the observed estimate. Smaller effects are harder to distinguish from random variation and therefore require more participants under the same assumptions.

These figures are not observed power. They do not describe the probability that the completed trial detected its true effect, and they should not be used to reinterpret the trial’s result as if they were its actual design. They are hypothetical planning estimates based on effect sizes observed in this trial. The record does not establish that the trial was originally planned using these assumptions or targets. For this continuous outcome, the figures refer to participants per arm; the general assumption note distinguishes these from time-to-event calculations, which would count total events.

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 = 0.198; pooled standard deviation σ = 0.753.
2. n = 2 × (1.96 + 0.842)² × 0.753² / 0.198² = 226.5, rounded up to 227 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 <- 0.1982                      # observed difference in means
sigma <- 0.752816059480511                     # 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(3257995)
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 = 227 (80% power), 304 (90% power)
 75% of observed effect: n per arm = 403 (80% power), 539 (90% power)
 50% of observed effect: n per arm = 906 (80% power), 1,213 (90% power)
power.t.test: 227.4 
Simulated power at n = 227 per arm: 0.799 (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 record reports sponsor ANOVA results for the primary comparisons of each salt with placebo and for the comparison between salts. The sponsor’s estimated mean differences for the placebo comparisons are 0.186 liters for maleate and 0.146 liters for acetate. Both reported 95% confidence intervals are above zero, and each reported p-value is p < 0.001. For maleate versus acetate, the sponsor reports a mean difference of -0.040 liters and a 95% confidence interval that includes zero; a p-value is not reported.

Simple unadjusted recalculations from the posted group means and standard deviations yield different estimates and wider intervals for the two comparisons with placebo. Those calculations do not incorporate the full crossover structure and are not equivalent to the sponsor’s ANOVA. The discrepancy is explicitly identified in the record. In keeping with that, the sponsor’s own analysis takes precedence over the recalculations.

The record names ANOVA as the method but does not provide the model specification, participant-level data, or other details needed to reproduce the sponsor analysis. The difference between the reported and recalculated results therefore cannot be attributed to a particular model feature with certainty. The sponsor’s estimates should be reported as the trial’s analyzed results, while the summary-based recalculations serve only as a limited comparison of what can be derived from the group summaries.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes or several comparisons. Even if each test is interpreted using its own nominal threshold, testing many hypotheses can increase the chance that at least one result appears notable by chance. Methods such as adjustment, a prespecified testing sequence, or clear identification of exploratory analyses can help readers understand how multiple results were handled.

The registry record lists 16 outcome measures and 15 posted secondary outcomes. It does not report whether the sponsor adjusted for multiplicity, used a testing hierarchy, or treated secondary outcomes as exploratory. The primary outcome description includes three treatment contrasts, but the registry record does not state how those contrasts were prioritized or whether adjustment was planned. The sponsor-reported p-values should therefore be read in the context of the analysis reported, without assuming a multiplicity procedure that is not described.

The registry record defines the primary pharmacodynamic analysis population as participants with available pharmacodynamic data who received any study drug and had no major protocol deviations with relevant impact on those data. That definition does not establish how many participants were excluded for each reason. The posted primary group summaries include different analyzed counts across treatments, but the record does not report a detailed participant flow, the amount or pattern of missing data, or reasons for missing measurements.

The handling of missing outcomes is also not reported in the registry record. It does not describe whether missing measurements were imputed, whether analyses used only available observations, or whether sensitivity analyses examined alternative assumptions. Nor does the record report results for a different analysis population, such as all randomized participants. These omissions limit assessment of how robust the estimated differences are to missingness or population choices. They do not establish that the analysis was inappropriate; they identify details that cannot be assessed from the registry record.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pharyngitis streptococcal (1.9%), sinusitis (1.9%).

The registry safety summary lists serious adverse event counts of 0 among 51 participants for indacaterol maleate 150 µg, 1 among 52 for indacaterol acetate 150 µg, and 0 among 53 for placebo. The record also lists no deaths in any of these groups. These counts describe the events recorded in the registry and should not be interpreted as a complete characterization of comparative safety.

The listed serious-event terms include pharyngitis streptococcal at 1.9% and sinusitis at 1.9%. The registry record does not provide further detail in the registry record about event timing, duration, clinical course, or the basis for determining relationship to treatment. The other adverse-event counts are 14 among 51, 7 among 52, and 9 among 53, respectively. These are separate from the serious-event counts and should not be conflated with them.

A crossover study exposes participants to more than one treatment over time, so safety counts across treatment groups may not represent independent groups of people. The registry record does not describe a safety analysis accounting for repeated exposure, nor does it give enough detail to compare event patterns by period. The figures are descriptive registry counts, not proof of equivalence or of a causal effect.

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

The primary registry results compare trough FEV1 after 14 days of treatment in each period. The sponsor’s ANOVA reports positive mean differences for each indacaterol salt versus placebo, with 95% confidence intervals above zero and p < 0.001 for both comparisons. The sponsor’s comparison between the salts has an interval that includes zero, and no p-value is reported for that contrast. These are the sponsor’s reported statistical results, not a measure of clinical importance.

The simple recalculations from the posted group summaries produce wider intervals that include zero for the salt-versus-placebo comparisons. Because the registry record flags a discrepancy, the sponsor’s own analysis takes precedence. The contrast between these analyses also shows that aggregate means and standard deviations do not necessarily reproduce a model-based crossover analysis. The registry record does not provide enough detail to independently resolve the difference.

Statistical evidence and clinical importance are distinct. A p-value does not tell readers how important an estimated difference is, and a confidence interval does not specify whether the values it contains would matter to patients. The registry record does not report a clinically important threshold for trough FEV1. It also does not report patient-reported outcomes or other information that would translate the endpoint differences into an assessment of lived experience.

The findings do not establish that either salt is clinically preferable, that the treatments are equivalent, or that the observed differences apply to every person with asthma. The trial enrolled 54 participants and reports treatment-specific analysis counts, and the registry record does not give a detailed account of missing data or participant flow. The results are specific to the measured outcomes, study population, treatment periods, and analyses described. They should not be extended beyond those limits.

18. Why This Trial Matters Statistically

This trial is statistically informative because it uses a crossover design to compare two indacaterol salts and placebo within a study that measured the same primary outcome across three treatment periods. Crossover designs can make within-participant comparisons possible, which is useful when participant characteristics may otherwise contribute substantial variation. At the same time, they require analyses that reflect the repeated treatment periods and the sequence in which treatments are received.

The registry record makes the distinction between an adjusted sponsor analysis and a simple comparison reconstructed from group summaries especially visible. The two approaches yield different estimates and different levels of uncertainty for the primary placebo comparisons. That difference underscores a general lesson: published group means and standard deviations do not always contain the information needed to reproduce a trial’s model-based result, particularly when outcomes are collected repeatedly within participants.

The trial also illustrates why statistical significance should not be treated as a complete interpretation. Sponsor-reported p-values and confidence intervals characterize evidence under the reported analysis, but they do not state whether the estimated differences are clinically important. The record does not report a clinical importance threshold. Secondary measures add useful context about pharmacokinetics and additional lung-function outcomes, but their multiplicity and the lack of a reported adjustment plan make them less definitive.

Finally, the registry record highlights the value of transparent reporting. Details about the ANOVA model, missing data, participant flow, multiplicity, and original sample-size planning would help readers assess reproducibility and robustness. Their absence does not invalidate the reported analysis, but it limits what can be independently evaluated.

19. Limitations

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

The registry record does not provide the full ANOVA specification for the primary outcome. Although ANOVA is named, the model terms, treatment of period and sequence, and handling of within-participant correlation are not reported. The record also does not report whether carryover was evaluated or how it would affect the analysis. These omissions are particularly relevant to a three-period crossover design.

The sponsor-reported primary estimates differ from simple unadjusted recalculations based on group summaries. The sponsor’s analysis takes precedence, but the discrepancy cannot be independently resolved using the registry information alone. Participant-level data and fuller model details are not reported, so the sponsor results cannot be reproduced from the available summaries.

The analysis population is restricted to participants with available pharmacodynamic data, who received study drug and had no major protocol deviations judged relevant to the data. The record does not report a detailed flow of participants, reasons for missing data, exclusions by treatment, the method for handling missing outcomes, or sensitivity analyses. These gaps limit assessment of whether missingness or population definition materially affected the results.

The record does not report a multiplicity adjustment or a hierarchy for the numerous outcome measures and comparisons. Nor does it report the original sample-size justification or the threshold for a clinically important difference in trough FEV1. These limitations constrain interpretation of secondary findings and clinical importance. The safety summary is also limited to counts and listed serious-event terms; further event-level detail and an analysis accounting for repeated treatment exposure are not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Two Orally Inhaled Indacaterol Salts in Adult Subjects With Asthma. — NCT03257995.
• Registry record last updated 2021-01-05; status last verified 2019-03.
• Results first posted 2019-03-29.
• 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

NCT03257995 is a completed phase 2 randomized, double-blind, placebo-controlled, three-period crossover study of indacaterol maleate, indacaterol acetate, and placebo in adults with asthma. The registry record lists an enrollment of 54 and quadruple masking. The primary endpoint was trough FEV1 in liters on Day 14 of each treatment period.

The sponsor reported ANOVA comparisons of each salt with placebo, with p < 0.001 for both, and a comparison between salts whose confidence interval includes zero. Simple unadjusted recalculations from posted group summaries differ; the sponsor’s own analysis takes precedence. The registry record does not report sufficient model detail to explain the discrepancy. Secondary outcomes address pharmacokinetics and additional lung-function measures. The record does not report the original sample-size justification, multiplicity plan, missing-data procedures, or a clinically important threshold for the primary outcome.