Tiotropium / Respimat One Year Study in COPD.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tiotropium / Respimat One Year Study in COPD. (NCT00387088), a registered phase 3 study. The primary outcome is Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 337.

2. Clinical Question

3. Trial Design

This was a Phase 3, parallel study with 3991 participants enrolled. Its recorded status is completed. The registry dates are 2006-09 for study start and 2009-01 for primary completion. The stated objective was to evaluate long-term efficacy and safety of tiotropium delivered by Respimat in COPD, with specific attention to COPD exacerbations.

The two described arms combined the study inhaler treatment with usual maintenance treatment. The tiotropium arm used tiotropium 5µg via Respimat, described as two inhalations of 2.5µg per day. The placebo arm used placebo via Respimat, described as two inhalations per day. Both descriptions exclude anticholinergic bronchodilators from usual maintenance treatment. The registry record lists Respimat as a device and tiotropium as a drug.

The record identifies a parallel model, but allocation is not stated. It also flags the arms as not being a like-for-like control comparison. Consequently, the arm labels and descriptions alone do not establish the allocation process or justify interpreting an arm contrast as a randomized treatment effect. The primary endpoint population description uses the term FAS and says it consisted of all randomised and treated participants, subject to exclusions. That population wording does not resolve the missing allocation information.

Alongside the primary FEV1 measure at Day 337, the registry lists outcomes covering FEV1 at Day 29 and Day 169, COPD exacerbation counts, participants with at least one exacerbation, time to first hospitalisation for COPD exacerbation, and hospitalisations for exacerbations. The registry record does not report a detailed statistical analysis plan, allocation method, or sample-size justification.

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 FAS was made up of all randomised and treated participants excluding 99 patients with questionable data. 133 participants from the FAS were excluded due to insufficient FEV1 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 Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 337, measured over Baseline and Day 337.

The primary endpoint was change from baseline in trough FEV1 at Day 337, expressed in litres. FEV1 is the volume of air forcibly expired in the first second of a forced expiration. A change-from-baseline endpoint compares a follow-up measurement with the participant’s baseline measurement; the registry record identifies the endpoint but does not report the resulting group estimates.

The trough timing is intended to capture lung function at the end of the dosing interval rather than soon after a dose. In this record, trough FEV1 is specifically defined as the measurement at the -10 min time point, 24 h after drug administration. Keeping the timing definition explicit matters because measurements taken at different points after dosing need not represent the same aspect of lung function.

The listed summary measure is a least-squares mean, with standard error as the dispersion measure. In general, a least-squares mean is a model-based mean, often adjusted for terms in an analysis model. The model terms and adjustment details are not reported in the registry record, so the precise interpretation of that estimate cannot be established. A standard error describes the estimated sampling variability of an estimate; it is not itself the range of plausible values for the underlying treatment effect.

FEV1 is a continuous measure, allowing the result to be expressed on its original litre scale. To evaluate the primary question, readers would need the arm estimates or a direct between-arm contrast, along with its uncertainty. Those endpoint results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a continuous measure: change from baseline in trough FEV1 at Day 337. It names the reported parameter as a least-squares mean and the dispersion measure as standard error. These labels describe the intended form of the summary, but the registry record does not give the estimates, the analysis model, or a direct treatment contrast. Statistical interpretation must therefore distinguish the endpoint definition from results that are not reported.

What does a least-squares mean represent?

In general, a least-squares mean is an estimated mean from a statistical model. It may account for covariates or other model terms, rather than simply averaging all observed values. Which terms were included, how baseline was incorporated, and how repeated measurements or other design features were handled are not reported in the registry record. Without those details, readers cannot determine exactly what model-based adjustment the endpoint estimates would represent.

A change-from-baseline measure is intended to describe how the outcome differs from its starting measurement. Analysing change can address baseline differences in a model, but the choice of method matters. The registry record does not state whether the analysis directly modelled change, adjusted follow-up values for baseline, or used another approach. It also does not state how any assumptions were checked.

How should standard error be read?

In general, a standard error quantifies sampling variability in an estimated quantity. It is useful for understanding how precisely a mean is estimated, but it is not the same as the spread of individual participants’ measurements. A confidence interval is commonly constructed from an estimate and its standard error, with the interval reflecting uncertainty under the statistical model and its assumptions. The confidence interval and standard error values for the primary endpoint are not reported in the registry record.

For a treatment comparison, separate arm means are not as informative as a direct contrast with an uncertainty interval. A contrast states the estimated difference according to a defined subtraction order; its uncertainty indicates how much the data and model leave unresolved. The registry record does not report the primary contrast or specify its direction convention. No direction or size should be inferred from the title or endpoint name.

What does the endpoint timing mean?

The endpoint is specifically trough FEV1. The registry defines this as the measurement at the -10 min time point at the end of the dosing interval, 24 h after drug administration. This timing standardizes the intended measurement relative to dosing. A value obtained close to dosing and one obtained at the end of the interval might answer different questions, so the time definition is part of the outcome itself, not a minor administrative detail.

The record lists FEV1 change at Day 29 and Day 169 as secondary outcomes, in addition to the primary measure at Day 337. It does not report the results at those times or describe a repeated-measures model. Whether outcomes at different visits were modelled jointly, separately, or with another approach is not reported in the registry record.

What do the planning illustrations mean?

In general, sample-size planning asks how many participants or events a future study might need under specified assumptions, including a target effect, variability, allocation, significance level, and desired power. The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. For time-to-event illustrations, the stated quantity is the total number of events; for other illustrations, it is participants per arm.

These are planning illustrations computed from the observed effect, not the trial’s own design. They should not be mistaken for the enrollment target, an explanation of how enrollment was chosen, or a measure of the probability that the trial result is correct. Power calculated using an observed effect is not observed power. Sample-size scenarios are conditional on their assumptions and do not repair absent outcome estimates or uncertainty measures.

The registry record does not report the original sample-size justification, a prespecified target effect, assumptions about variability, or the statistical analysis plan. It also does not report whether interim analyses were conducted. These omissions prevent readers from judging how the trial’s planning related to its final analysis. The posted planning assumptions can explain the meaning of the illustrations, but they cannot establish the protocol’s original statistical choices.

Why can count outcomes require different methods?

In general, event counts and continuous measurements have different statistical properties. Exacerbation counts can be unevenly distributed: many participants may have few events while some have several. If variability exceeds what a simple count model assumes, over-dispersion can make standard errors too small unless the analysis accounts for it. Exposure-adjusted rates can also account for different observation time, while a naïve count summary does not make the same adjustment. The registry lists exposure-adjusted and naïve estimates, but does not report their values or the models used.

Time to first hospitalisation is a time-to-event outcome. In general, such analyses account for the timing of the first event and may also need to handle participants whose follow-up ends before an event. The registry does not describe censoring rules or the time-to-event model. These are general methodological considerations, not claims about the methods used in this study.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Tiotropium", "Placebo")
n   <- c(1889, 1870)
m   <- c(0.119, 0.018)
sp  <- c(0.007, 0.007)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Tiotropium  1889  0.119  0.304  0.105  0.133
CARM  Placebo  1870  0.018  0.303  0.004  0.032

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary FEV1 outcome and multiple secondary outcomes, including FEV1 at other follow-up times, several exacerbation measures, and hospitalisation outcomes. When a study evaluates multiple outcomes or time points, the chance of at least one apparently notable result can increase if no adjustment or hierarchy is used. In general, a prespecified testing strategy can define which outcome is primary and how other tests are interpreted.

The registry record does not report a multiplicity adjustment, a hierarchy for secondary outcomes, or a detailed statistical analysis plan. It is therefore not possible to determine whether the listed outcomes were treated as confirmatory, exploratory, or subject to a prespecified family-wise error approach. Nor is it possible to infer that a correction was or was not performed. The number of listed outcomes alone does not reveal the testing strategy.

Missing-data handling is also important for a change-from-baseline endpoint, particularly when not every participant contributes endpoint measurements. The FAS description states that it included all randomised and treated participants except 99 patients with questionable data, and that 133 participants from the FAS were excluded due to insufficient FEV1 data. These exclusions are reported, but the reasons for questionable data, the pattern of insufficient measurements, and any imputation or sensitivity analyses are not reported in the registry record.

The record does not explain whether participants with incomplete follow-up were analysed using observed measurements only, model-based methods, imputation, or another approach. It also does not report the assumptions used to handle missing outcomes or whether robustness to those assumptions was examined. The stated analysis population therefore identifies exclusions but does not, by itself, establish how missing observations were handled or how those decisions affect the estimate.

The population description uses FAS and refers to randomised and treated participants, while allocation is not stated elsewhere and the comparison is flagged as not like-for-like. The registry record does not explain this distinction. Readers should keep the described analysis population separate from assumptions about the trial’s allocation or the causal interpretation of its comparison.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chronic obstructive pulmonary disease (7.9%), pneumonia (1.9%), infective exacerbation of chronic obstructive airways disease (0.9%), respiratory failure (0.6%), lung neoplasm malignant (0.5%).

The registry reports serious adverse events affecting 342 participants at risk of 1952 in the tiotropium group and 336 at risk of 1965 in the placebo group. It reports other adverse events affecting 866 of 1952 and 926 of 1965, respectively. These figures are participant counts in the recorded groups. They should not be read as event rates or as a formal estimate of the difference between treatments; the registry record does not provide a comparative safety analysis or uncertainty interval for these counts.

The listed serious adverse event terms include Chronic obstructive pulmonary disease at 7.9%, Pneumonia at 1.9%, Infective exacerbation of chronic obstructive airways disease at 0.9%, Respiratory failure at 0.6%, Lung neoplasm malignant at 0.5%, and Dyspnoea at 0.5%. The registry record does not specify the group attribution or denominator for these term percentages, so they should not be assigned to an arm or interpreted as group-specific rates.

Death counts are not reported in the registry record. The counts also do not establish causation: a serious adverse event recorded during a study is not necessarily caused by the intervention. Interpretation of comparative safety would require the event definitions, observation periods, group-specific details, and analysis methods, which are not reported in the registry record.

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

The registry describes a study of tiotropium delivered by Respimat in participants with COPD, with a primary endpoint of change from baseline in trough FEV1 at Day 337. It also describes treatment and placebo inhaler regimens, usual maintenance treatment, and the exclusions applied to the endpoint population. These details establish what the primary outcome was intended to measure, but they do not establish the outcome itself.

The primary endpoint estimates, treatment contrast, and uncertainty measures are not reported in the registry record. As a result, the posted information does not show whether the primary endpoint changed in either arm, whether the arms differed, or how precisely any difference was estimated. A study objective is not a result, and the name of an endpoint cannot substitute for its estimate.

The record does include serious and other adverse-event participant counts. Those figures describe recorded counts in each group, but do not by themselves quantify a causal effect or provide a complete comparison of safety. The list of serious event terms includes percentages without a stated group attribution or denominator. Death counts are not reported in the registry record.

There are also limits on interpreting any arm comparison. Allocation is not stated, and the record explicitly flags the arms as not being a like-for-like control comparison. Although the FAS description says participants were randomised and treated, the registry record does not reconcile that wording with the allocation qualification. A causal interpretation cannot be settled from these details alone.

The planning illustrations are not evidence that a target effect was observed or that the study had a particular probability of detecting it. They are planning scenarios based on the observed effect and stated assumptions, rather than a report of the trial’s design justification or observed power. Overall, the registry record supports a description of the intended endpoint, study arms, analysis-population exclusions, and posted safety counts, but it does not support a quantitative conclusion about the primary efficacy result.

14. Why This Trial Matters Statistically

This study is statistically notable for the gap between a clearly named primary endpoint and the absence of its numerical results in the registry record. The endpoint is defined with a specific measurement time and summary measure, and the analysis population is described with explicit exclusions. Those details help readers understand the intended question. Without the arm estimates and their uncertainty, however, the central statistical comparison cannot be evaluated.

The record also illustrates why a study label does not answer questions about design. It identifies a Phase 3 parallel study and describes tiotropium and placebo arms, yet allocation is not stated and the comparison is flagged as not being like-for-like. The FAS description refers to randomised and treated participants, but the registry does not explain the apparent tension. Clear reporting of allocation and the basis of the comparison is important for judging whether an observed difference can be attributed to treatment.

For clinical researchers and biostatisticians, the endpoint details show the value of specifying timing and scale. Trough FEV1 at the end of the dosing interval is not interchangeable with an unspecified FEV1 reading. Reporting the measure alongside the contrast, confidence interval, and analysis method would allow readers to assess both direction and precision.

The registry also lists event-count and time-to-event outcomes, which bring different modelling considerations from a continuous lung-function endpoint. Distinguishing exposure-adjusted from naïve event summaries is useful, but model details and outcome estimates are not reported. Planning illustrations should likewise be kept distinct from observed evidence and from the original sample-size rationale. Together, these reporting features make the record useful for identifying the intended questions while highlighting what remains unreported for statistical interpretation.

15. Limitations

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

The most consequential limitation for interpretation is that the primary FEV1 estimates and between-arm contrast are not reported in the registry record. The corresponding uncertainty measures are also absent. Without them, the treatment effect’s direction, size, and precision cannot be assessed. The registry’s description of a least-squares mean and standard error does not provide the values or explain the model that generated them.

Allocation is not stated, and the registry flags the comparison as not being a like-for-like control comparison. The FAS description refers to randomised and treated participants, but no explanation is reported for the qualification about allocation and comparability. This makes it difficult to determine the basis for causal interpretation of an arm difference.

For the primary outcome, the record reports exclusions of 99 patients with questionable data and 133 participants with insufficient FEV1 data. It does not report the reasons for questionable data, the distribution or timing of missing measurements, the missing-data method, or sensitivity analyses. The analysis population information therefore does not establish how missingness may have affected the result.

The record does not report a statistical analysis plan, model specification, multiplicity strategy, original sample-size justification, or whether interim analyses occurred. Results for the listed secondary outcomes are not reported in the registry record. Safety reporting is also limited: death counts are absent, and the serious adverse event term percentages lack stated group attribution and denominator. These are limitations of the available registry record, not evidence that the omitted procedures or analyses were absent from the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Tiotropium / Respimat One Year Study in COPD. — NCT00387088.
• Registry record last updated 2014-05-16; status last verified 2013-09.
• Results first posted 2010-01-22.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00387088 is a completed Phase 3 parallel study of tiotropium delivered by Respimat in COPD, with 3991 participants enrolled. The recorded study start is 2006-09 and primary completion is 2009-01. The primary endpoint was change from baseline in trough FEV1 at Day 337, measured in litres and summarized as a least-squares mean with standard error.

The endpoint population description excludes 99 patients with questionable data and 133 participants with insufficient FEV1 data. Primary outcome estimates and a treatment contrast are not reported in the registry record. Allocation is not stated, and the record flags the arm comparison as not like-for-like. Serious and other adverse-event counts are posted for both groups, while death counts are not reported in the registry record.