Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients (NCT01533922), a randomized phase 3 study. The primary outcome is Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap.

2. Clinical Question

3. Trial Design

The registry describes NCT01533922 as a completed, randomized, double-blind, phase 3, incomplete crossover trial. It enrolled 295 participants with COPD. Five treatment arms were included: placebo, olodaterol 5 µg, tiotropium 5 µg, and two tiotropium–olodaterol fixed-dose combinations. The combination doses were tiotropium 2.5 µg plus olodaterol 5 µg and tiotropium 5 µg plus olodaterol 5 µg. Treatments were delivered using the Respimat inhaler.

The official title describes a 4-period study in which each participant did not necessarily receive every treatment. The registry states that allocation was randomized and masking was double. The posted primary outcome timeframe is 6 weeks, and the primary means are adjusted means from a Mixed Effects Model Repeated Measures analysis. The registry’s reported comparisons are also identified as mixed models analyses.

Enrollment is not the same as the number contributing to every analysis. For the primary endpoint, the Full Analysis Set included participants from the treated set who had a study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints, after application of data-handling rules that could set measurements to missing. The number contributing varied by treatment outcome; the posted primary analysis counts range from 211 to 219.

The registry lists a start date of 2012-03, primary completion in 2013-11, and status as completed. Details such as the sequence assignment procedure, period-specific treatment administration, washout procedures, and original statistical design assumptions are not reported in the registry record. A crossover design can make within-participant comparisons possible, but interpreting its model-based estimates depends on the analysis accounting appropriately for the repeated treatment periods.

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 was a randomised, 4-period incomplete block cross-over trial. 295 patients were randomized to one of five treatments sequences and treated. It was a double-blind trial in which each treatment period lasted 6 weeks with a washout period of 21 days between each.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) : This patient set included all patients in the TS who had the study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints. Assignment to the FAS was done after implementation of any data handling rules,which set measurements to missing.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Treated Set (TS) : This patient set included all patients of the Randomised Set (RS : patients who signed the informed consent form and were also randomised, regardless of whether the patient was treated with study medication or not) who were dispensed study medication and were documented to have taken at least 1 dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap, measured over 6 weeks.

The primary endpoint was inspiratory capacity (IC) at rest, measured before constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity. The unit was litres, the timeframe was 6 weeks, and the posted values are adjusted means from a Mixed Effects Model Repeated Measures model. The registry defines maximal work capacity, or Wcap, as the maximum work rate achieved for at least 30 seconds during incremental cycle ergometry performed at Visit 1.

IC is a lung-volume measure: it records the volume that can be inhaled from the end of a normal expiration to a full inspiration. In general, resting IC is used as a physiological indicator relevant to lung hyperinflation, which is why it fits the trial’s stated interest in both hyperinflation and exercise endurance. The assessment was made before the exercise test, rather than being a direct measure of how long participants exercised.

The endpoint therefore addresses a specific question about resting inspiratory capacity after treatment, in the context of a defined exercise-testing procedure. It does not by itself measure exercise endurance time, symptom burden in daily life, or long-term changes. The registry’s stated primary endpoint is IC; exercise endurance is part of the trial’s broader rationale, not the primary outcome reported in these results.

Adjusted means are model-based estimates rather than simple raw averages. Their interpretation depends on the model and analysis population. The registry describes the model as MMRM and reports standard errors for the arm means, but further details about model terms and covariance structure are not reported in the registry record.

7. Results Posted in the Registry

• Olodaterol 5 µg: mean 2.57 versus 2.44 on control; difference 0.13 (95% CI 0.05 to 0.20), standardized effect d = 0.32; z-test p = <0.001.
• Tiotropium 5 µg: mean 2.57 versus 2.44 on control; difference 0.13 (95% CI 0.06 to 0.21), standardized effect d = 0.33; z-test p = <0.001.
• Tiotropium + Olodaterol 2.5/5: mean 2.66 versus 2.44 on control; difference 0.22 (95% CI 0.14 to 0.29), standardized effect d = 0.55; z-test p = <0.001.
• Tiotropium + Olodaterol 5/5: mean 2.69 versus 2.44 on control; difference 0.25 (95% CI 0.17 to 0.32), standardized effect d = 0.62; z-test p = <0.001.

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.

Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity

• 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:
  • Olodaterol 5 µg: mean 0.02 versus 0.02 on control; difference -0.00 (95% CI -0.00 to 0.00), standardized effect d = -0.14; z-test p = 0.157.
  • Tiotropium 5 µg: mean 0.02 versus 0.02 on control; difference -0.00 (95% CI -0.00 to 0.00), standardized effect d = -0.14; z-test p = 0.157.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Olodaterol 5 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 Tiotropium 5 µg and the control. The interval gives the range of effects that remain compatible with the data.

Forced Expiratory Volume in 1 Second (One Hour Post-dose)

• 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:
  • Olodaterol 5 µg: mean 1.69 versus 1.50 on control; difference 0.19 (95% CI 0.16 to 0.23), standardized effect d = 1.01; z-test p = <0.001.
  • Tiotropium 5 µg: mean 1.71 versus 1.50 on control; difference 0.21 (95% CI 0.17 to 0.25), standardized effect d = 1.09; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Olodaterol 5 µg 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 Tiotropium 5 µg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry posts two secondary outcomes: the slope of intensity of breathing discomfort during constant work rate cycle ergometry, and FEV1 measured one hour post-dose. The listed summaries show different patterns across outcomes and treatment comparisons. In general, the secondary outcomes add physiological and symptom-related context to the primary resting IC result, but they do not measure the same construct and cannot be treated as interchangeable evidence.

The sponsor’s reported secondary analyses include selected contrasts rather than a complete set of inferential results for every treatment pairing. The registry also reports summary means and standard errors for the arms. Those descriptive summaries can help identify the direction of the posted means, but inference should rely on the reported model analyses where available. The registry record does not report a unified analysis across the secondary outcomes or a complete account of which secondary comparisons were prespecified.

Secondary endpoints commonly carry less weight than a primary endpoint because they may be tested in addition to the main trial question, and many comparisons can increase the chance of findings arising by chance. Unless a prespecified multiplicity procedure controls that issue, individual secondary p-values should not be interpreted as if they were the sole planned test. The registry record does not report a multiplicity adjustment for these secondary analyses.

Accordingly, the secondary findings should be considered alongside, rather than substituted for, the primary endpoint. They provide supplementary evidence about outcomes relevant to breathing and lung function, but the posted record does not establish how they were ranked within the protocol or whether they were intended to support formal confirmatory claims. Their interpretation is also limited by incomplete reporting of comparison-level model details and analysis populations.

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

• Slope of the Intensity of Breathing Discomfort During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity
• Forced Expiratory Volume in 1 Second (One Hour Post-dose)

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports a randomized, double-blind, incomplete crossover design. In general, a crossover trial compares treatments within participants across different periods, while an incomplete crossover means each participant does not receive every treatment. This can use participant-level information efficiently because a participant may serve as their own reference for some comparisons. It also means that period, sequence, and within-participant correlation can matter to the analysis. The registry’s summary does not describe the detailed handling of these design features.

What does the mixed model contribute?

The primary endpoint means are described as adjusted means from a Mixed Effects Model Repeated Measures (MMRM) model. In general, a repeated-measures mixed model accounts for measurements that are related because they come from the same participant, and can estimate treatment means while accounting for specified model terms. “Adjusted” means the estimates come from the fitted model, rather than simply averaging all recorded values without regard to the analysis structure. The registry reports mixed models analyses for treatment contrasts, but the complete model specification, including all covariates and period or sequence terms, is not reported in the registry record.

The model-based contrast compares estimated endpoint values between two treatments. For example, the reported contrast of 0.244 litres for the 5/5 combination versus placebo is a difference in final values from the sponsor’s mixed-model analysis. It is not a within-person change from baseline. The registry gives an interval and p-value for these contrasts, but does not provide the full set of model diagnostics or assumptions needed to independently reproduce the analysis.

How should means and standard errors be read?

A mean summarizes the central value of a continuous outcome. The primary outcome is measured in litres, and its reported arm means are adjusted. The standard error describes the precision of an estimated mean: in general, a smaller standard error indicates less sampling uncertainty in that estimate. It is not the same as the standard deviation, which describes variability among individual observations. The posted primary arm standard errors are 0.027 litres. The registry does not report individual-level distributions or standard deviations for this endpoint.

The recalculated comparisons use the posted summary means and standard errors to form simple, unadjusted treatment contrasts. These are useful as a check on the direction and approximate scale of the reported results, but they do not reproduce a crossover mixed model. In particular, the summary-statistic calculation does not use participant-level pairing or the full repeated-measures structure. This is why sponsor-reported model-based comparisons are the primary inferential results for this trial.

What does a confidence interval say?

A confidence interval describes statistical uncertainty around an estimated contrast. In general, a narrower interval indicates greater precision, while a wider interval indicates that a broader range of values is compatible with the data and model. The sponsor’s primary contrasts are reported with 95% confidence intervals. For the 5/5 combination versus placebo, the interval is 0.191 to 0.298 litres. This interval lies above zero, indicating that the data and reported model estimate a positive contrast for that comparison. It does not alone establish clinical importance.

A p-value measures how incompatible the observed result is with a specified null hypothesis, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor a measure of effect size. For primary comparisons, the registry reports p-values below < 0.001. The record does not report a prespecified multiplicity adjustment for the set of comparisons, so the p-values should be read with that limitation in mind.

Why can over-dispersion matter in general?

For continuous outcomes, the precision of estimates depends in part on variability. In other statistical settings, over-dispersion means that observed variability exceeds what a model assumes; if not handled appropriately, standard errors can be too small and intervals too narrow. This is a general statistical consideration, not a reported finding about this trial. The registry record does not report an over-dispersion assessment for the continuous primary endpoint.

There are multiple treatment comparisons and several outcomes. In general, making many statistical tests increases the chance that at least one result appears notable by chance. Whether and how that issue was addressed depends on the trial’s prespecified analysis plan. The registry record does not report the full multiplicity strategy or the trial’s original statistical analysis plan. Therefore, no claim about formal control of the overall false-positive rate can be made from the posted record alone.

11. Confidence Intervals and Precision

The registry’s sponsor-reported primary comparisons include 95% confidence intervals. For the 5/5 combination versus placebo, the estimated difference was 0.244 litres, with an interval from 0.191 to 0.298. For the 2.5/5 combination versus placebo, the estimated difference was 0.218 litres, with an interval from 0.164 to 0.271. Both intervals lie above zero, so the reported model estimates favor higher IC values in the combination arms for these comparisons. This description concerns the outcome values, not a claim about clinical benefit.

The width of an interval conveys precision. In general, a narrower interval is more precise because it allows a smaller range of estimates; a wider interval leaves more uncertainty about the contrast’s magnitude. The model-based intervals for the primary comparisons are not interchangeable with recalculated intervals based on arm-level summaries. For the 5/5 combination versus placebo, the simple recalculation gives an interval from 0.170 to 0.320, which is wider than the sponsor-reported interval. This difference is consistent with the recalculation not using the crossover model’s participant-level structure.

The posted primary arm means each have a standard error of 0.027 litres. Standard errors quantify uncertainty in estimated means, not the spread of individual participant values. Because the registry does not give standard deviations or participant-level observations for the primary endpoint, the individual variation and distribution cannot be fully assessed from these summaries.

Confidence intervals do not indicate whether an observed difference matters to patients. The registry record does not state a clinically important threshold for inspiratory capacity. Nor does the interval account for uncertainty about unreported analysis choices or missing-data assumptions. It expresses statistical uncertainty conditional on the reported model and data handling.

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 sample-size figures are planning illustrations based on observed effects, not the trial’s original design calculations. For the continuous outcomes shown, the figures are participants per arm; they are not total events. The planning assumptions listed in the registry analysis are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario asks what sample size would be needed to detect a stated fraction of the observed effect. The original trial’s design assumptions and sample-size justification are not reported in the registry record.

The 80% power column indicates the number of participants per arm under those assumptions for an 80% chance of detecting the specified effect if that effect is the true one. The 90% power column gives the corresponding planning number for a 90% chance. In general, the higher power target requires more participants, and smaller effects require more participants than larger effects. For instance, the rows that plan for 75% or 50% of an observed effect represent smaller target effects than planning for 100% of that observed effect.

These figures are not observed power. They are hypothetical planning quantities calculated from the observed effect and stated assumptions. They should not be read as evidence that the completed trial did or did not have adequate power for its actual design, especially because the trial used an incomplete crossover structure and the illustrations assume equal allocation between two arms. No power calculation can replace interpretation of the estimated contrast and its confidence interval.

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 = 0.126; pooled standard deviation σ = 0.394.
2. n = 2 × (1.96 + 0.842)² × 0.394² / 0.126² = 153.2, rounded up to 154 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 <- 0.126                      # observed difference in means
sigma <- 0.393599104825137                     # 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(1533922)
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 = 154 (80% power), 206 (90% power)
 75% of observed effect: n per arm = 273 (80% power), 365 (90% power)
 50% of observed effect: n per arm = 613 (80% power), 821 (90% power)
power.t.test: 154.1 
Simulated power at n = 154 per arm: 0.802 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The registry reports sponsor analyses using mixed models. For the primary comparison of tiotropium plus olodaterol 5/5 against placebo, the sponsor reported a mean difference of 0.244 litres, with a 95% confidence interval from 0.191 to 0.298 and p < 0.001. The registry also reports the 5/5 combination compared with olodaterol 5 µg and tiotropium 5 µg, as well as comparisons for the 2.5/5 combination.

The simple recalculation for the 5/5 combination versus placebo is 0.245 litres, with a 95% interval from 0.170 to 0.320. The close point estimates are not evidence that the two analyses are equivalent: the recalculation uses arm-level summaries and does not reproduce the mixed-model crossover analysis. Its interval is wider, reflecting a different calculation and assumptions. The sponsor’s model-based analysis uses the registry-reported method for this trial and is the more appropriate estimate to emphasize.

The posted record does not flag a discrepancy between the recalculation and sponsor analysis. The model-based results therefore remain the primary source for interpreting the trial contrasts. The recalculation is best viewed as a transparent, simple check rather than a replacement or independent confirmation of the full crossover model.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists secondary outcomes, but it does not report the full statistical analysis plan or a prespecified multiplicity strategy. This matters because the posted results include multiple treatment comparisons, including combinations versus placebo and single-agent treatments, and more than one outcome. In general, testing many hypotheses without adjustment increases the probability of at least one apparently positive result when all null hypotheses are true. The record does not establish whether the sponsor controlled that overall risk through a hierarchy, adjustment, or another procedure.

The reported p-values and confidence intervals should therefore be read as results for the specific comparisons and model analyses described, not as proof that every possible comparison has been protected against multiplicity. The absence of a reported adjustment is not proof that none was used in the full protocol; the details are not reported in the registry record.

Missing-data handling is partly described for the primary Full Analysis Set. Participants had to have a study baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints, after application of data-handling rules that could set measurements to missing. This describes eligibility for that analysis set, but it does not provide the number or reasons for missing measurements, the missingness assumptions, or sensitivity analyses. Those details are not reported in the registry record.

The registry does not report a complete account of analysis populations for every secondary outcome, nor does it explain how incomplete crossover treatment sequences were represented in each analysis. The registry identifies the primary outcome means as adjusted MMRM estimates and lists sponsor mixed-model comparisons, but model terms, covariance choices, diagnostics, and sensitivity analyses are not reported. These omissions limit independent assessment of robustness, especially where repeated treatment periods and missing measurements can influence estimates.

16. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.9%), chronic obstructive pulmonary disease (0.9%), angina pectoris (0.5%), squamous cell carcinoma of skin (0.5%), transient ischaemic attack (0.5%).

The registry lists serious adverse events and other adverse events by treatment group, together with the number at risk. For serious adverse events, the posted figures are 4 of 222 for placebo, 3 of 217 for olodaterol 5 µg, 8 of 226 for tiotropium 5 µg, 5 of 222 for the 2.5/5 combination, and 6 of 226 for the 5/5 combination. These are counts within the registry’s listed group denominators; they should not be treated as adjusted comparisons of risk.

The registry also reports other adverse events in the respective groups, but these are distinct from serious adverse events. Serious-event terms listed include pneumonia and chronic obstructive pulmonary disease at 0.9% each, and angina pectoris, squamous cell carcinoma of skin, transient ischaemic attack, and bradycardia at 0.5% each. These term frequencies provide context but do not establish that a treatment caused an event.

Death counts are not reported in the registry record. The safety data do not include enough information in this summary to evaluate duration of exposure, event timing, recurrent events, or adjusted between-treatment differences. In an incomplete crossover study, group-level counts should also be interpreted in the context of treatment exposure and the trial’s design, details of which are limited in the posted record. These figures are descriptive and are not a substitute for a full safety analysis.

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

The posted primary results show higher adjusted mean resting inspiratory capacity after 6 weeks in the two tiotropium–olodaterol combination arms than in the placebo arm. The sponsor’s mixed-model analyses also report positive differences for the combinations compared with olodaterol alone and tiotropium alone. The confidence intervals for these reported primary comparisons lie above zero. These statements describe the trial’s measured outcome and statistical estimates.

They do not establish how important the differences are to participants. The registry does not report a threshold for a clinically meaningful change in inspiratory capacity. Nor does this primary endpoint directly show how long participants could exercise, how symptoms changed in everyday life, or whether health outcomes changed over a longer period. Although exercise endurance and lung hyperinflation inform the trial’s question, the primary result is a resting IC measure taken before a specified cycling test.

The analyses also do not by themselves establish a causal explanation for the differences beyond the trial’s randomized treatment comparisons, or show whether effects persist beyond the reported 6-week timeframe. The registry record does not report longer-term results, detailed missing-data sensitivity analyses, or a complete multiplicity strategy. Those limitations affect how broadly the findings can be interpreted.

Finally, the trial’s results should not be reduced to whether a p-value crosses a threshold. The size and precision of the estimated difference, the endpoint’s clinical interpretation, the study design, and the completeness of reporting all matter. The registry’s model-based analyses are the relevant comparisons for this crossover trial; simple recalculations are supportive checks only and do not reproduce the sponsor’s repeated-measures model.

18. Why This Trial Matters Statistically

This trial illustrates why the design and analysis structure matter when interpreting clinical results. The registry describes a randomized, double-blind, incomplete crossover study with 5 treatment arms and 4 periods. Because participants may contribute information under more than one treatment, the comparison is not equivalent to an ordinary two-arm parallel trial. A model that accounts for repeated measurements can produce estimates that differ in precision from simple calculations using arm-level summaries.

The distinction is visible in the primary comparison of the 5/5 combination with placebo. The sponsor’s mixed-model estimate is 0.244 litres, while the simple recalculation is 0.245 litres. The point estimates are close, but their intervals differ. This illustrates that matching point estimates do not mean the analyses use the same information or assumptions. For a crossover study, participant-level structure can be important to the uncertainty estimate.

The trial also shows why endpoint definition matters. Inspiratory capacity at rest before an exercise test is a physiological outcome relevant to the stated question about hyperinflation, but it is not the exercise endurance time itself. Keeping that distinction clear prevents a result on one measured construct from being generalized to another.

Finally, precision, multiplicity, and reporting completeness are part of statistical interpretation. The sponsor’s primary intervals are informative about uncertainty for the stated comparisons, while unreported multiplicity and missing-data details limit assessment of the full inferential picture. Reading the estimates in this context is more informative than relying on a single significance result.

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 leaves important design and analysis details unspecified. It identifies a 4-period incomplete crossover, but does not report treatment sequences, washout procedures, period-specific handling, or the complete model specification. These details matter because treatment order and repeated measurements may affect crossover estimates and their precision.

The primary outcome population is described through eligibility rules, including a baseline and at least 1 evaluable post-dose measurement for 1 of the primary endpoints. However, the record does not give a complete account of missing observations, reasons for missingness, assumptions about missing data, or sensitivity analyses. It is therefore not possible from the posted summary to assess how robust results are to alternative missing-data assumptions.

The registry does not report the original sample-size justification, the full analysis plan, or a multiplicity procedure. The sample-size illustrations based on observed effects cannot fill those gaps or show the planned power of the original design. In addition, the primary endpoint is a specific physiological measure; the registry does not report a clinically important threshold for interpreting its magnitude.

Secondary outcome reporting is incomplete at the comparison level, and the record does not establish the hierarchy or confirmatory status of those analyses. Safety summaries are descriptive, with limited information about exposure duration, timing, recurrent events, and adjusted comparisons. Death counts are not reported in the registry record. Together, these limitations counsel against extending the posted results beyond the measured outcomes, comparison set, and timeframe.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients — NCT01533922.
• Registry record last updated 2015-09-15; status last verified 2015-08.
• Results first posted 2015-09-15.
• 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

NCT01533922 is a completed, randomized, double-blind phase 3 study in COPD, described as a 5-treatment-arm, 4-period incomplete crossover trial. The registry reports 295 participants enrolled and a 6-week primary outcome timeframe. Treatments included placebo, olodaterol 5 µg, tiotropium 5 µg, and tiotropium–olodaterol combinations at 2.5/5 and 5/5.

The primary endpoint was adjusted mean inspiratory capacity at rest before constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity. Sponsor-reported mixed-model comparisons found positive differences for the combinations versus placebo and the single-agent arms. Simple recalculations from the arm summaries are not substitutes for the crossover model.

The registry also posts secondary outcomes and adverse-event counts. Interpretation is constrained by unreported details on multiplicity, the complete analysis plan, missing-data assumptions, model specification, and the original sample-size justification. The posted results describe short-term measurements and do not establish clinical importance beyond the endpoints and timeframe reported.