A Trial Comparing Treatment With Tiotropium Inhalation Capsules to Combivent Inhalation Aerosol in COPD Patients.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial Comparing Treatment With Tiotropium Inhalation Capsules to Combivent Inhalation Aerosol in COPD Patients. (NCT00359788), a registered phase 4 study. The primary outcome is Change From Baseline in Trough FEV1 (Forced Expiratory Volume in 1 Second) at 12 Weeks.

2. Clinical Question

The registry record frames the study around efficacy and safety in people with COPD who were already prescribed Combivent MDI. The primary endpoint is a lung-function measure: trough FEV1, measured in liters and taken 10 minutes before drug administration. The record names the endpoint and its assessment timeframe, but the numerical group results and the between-group estimate are not reported in the registry record. Therefore, the record does not establish the direction or size of any difference in this primary outcome.

The clinical question is a comparison between treatment strategies over 12 weeks, not a comparison with no treatment. The descriptions identify the medicines and dosing schedules, but do not report enough detail to assess adherence, treatment changes, or the extent to which participants followed the intended regimens. The official title calls the study randomized and double-blind, while the registry record does not state the allocation method. That omission limits how confidently the comparison can be interpreted as randomized.

3. Trial Design

The registry record identifies a phase 4, parallel-group study with an enrollment of 349 participants and a completed status. Its recorded start is 2006-07 and its primary completion is 2008-04. The official title describes a randomized, double-blind comparison over 12 weeks. However, the allocation method is not stated in the registry record, so the randomization process cannot be verified from the record. Details of how blinding was implemented or maintained are not reported in the registry record.

The treatment groups are tiotropium and Combivent (ipratropium/albuterol). The study summary describes tiotropium HandiHaler 18 micrograms daily and Combivent Metered Dose Inhaler, chlorofluorocarbon inhalation aerosol, at 2 actuations four times a day. The study population is described as people with COPD currently prescribed Combivent MDI. Because both groups receive an active medicine, the question concerns the relative outcomes under the two treatment regimens rather than treatment versus placebo.

The primary outcome is change from baseline in trough FEV1 at 12 weeks. Other listed outcomes include trough FEV1 at 6 weeks; average hourly FEV1 AUC0-6 on Day 1 and at Week 6; peak FEV1 on Day 1 and at Weeks 6 and 12; and changes in FVC measures. The record lists 114 outcome measures and 114 analyses, but does not report the full analysis plan or explain how those outcomes were organized or prioritized beyond identifying the primary endpoint.

The record’s characterization of the comparison requires caution: although the official title says randomized, the allocation method is not stated, and the record notes that the arms are not a like-for-like control comparison. The basis for that characterization is not reported in the registry record. The protocol, sample-size justification, interim analysis plan, and detailed conduct information are also 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: Participants analyzed belonged to the Full Analysis Set (FAS) and included all patients randomized, treated with study medication and had baseline FEV1 and at least one post-dose trough FEV1.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Trough FEV1 (Forced Expiratory Volume in 1 Second) at 12 Weeks, measured over Baseline and 12 Weeks.

The primary endpoint is change from baseline in trough FEV1 at 12 weeks, measured in liters. FEV1 is the volume of air a person can forcefully exhale in the first second of an expiration. Trough refers to a measurement taken near the low point of a medicine’s dosing interval; in this study, the registry record specifies that it was measured 10 minutes before drug administration. The endpoint therefore focuses on lung function at a defined point before a dose, rather than on the peak response after administration.

Change from baseline expresses how the measurement at follow-up differs from the participant’s baseline measurement. Comparing such changes between groups can describe whether the groups followed different average trajectories over the study period. The record identifies the reported summary as a least-squares mean with standard error. In general, a least-squares mean is a model-based mean, but the model and any covariates used for this endpoint are not reported in the registry record. A standard error describes the precision of an estimated mean; it is not a description of how widely individual participants’ measurements vary.

FEV1 is used as a continuous lung-function measure in COPD studies. A pre-dose trough assessment can be useful when the question concerns lung function before the next scheduled administration. The endpoint definition does not by itself establish whether an observed change is clinically important. The primary endpoint’s group estimates, standard errors, and comparative estimate are not reported in the registry record, so the magnitude and precision of the observed effect cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean describe?

The primary endpoint is labeled a least-squares mean, a statistical summary commonly obtained from a model. In general, such a mean can represent an estimated group average after accounting for terms included in the model. Which model was used, whether baseline values or other covariates were included, and how repeated observations were handled are not reported in the registry record. The label alone does not identify the adjustment strategy or allow the estimate to be reconstructed.

The record also labels the dispersion measure as a standard error. In general, the standard error describes uncertainty in an estimated mean due to sampling variability. It is different from a standard deviation, which describes variability among individual observations. A standard error is most informative when read with the mean and, where available, a confidence interval. The numerical primary estimates and their standard errors are not reported in the registry record.

What does a confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the observed data under a specified method and its assumptions. Its width communicates precision: a narrower interval indicates less statistical uncertainty than a wider interval. It does not show the range of outcomes for every participant, and it does not on its own determine whether an effect matters clinically. The registry record does not report a confidence interval for the primary treatment comparison.

A comparison of two group means needs an estimate of the contrast and a measure of its uncertainty. Reporting only a group summary would not fully answer whether the groups differed, because the comparison also depends on the precision of both estimates and the method used to analyze them. The record’s primary outcome description does not include a numerical contrast, so a treatment difference cannot be characterized.

Why do analysis populations matter?

The stated Full Analysis Set includes randomized participants who received study medication and had baseline FEV1 and at least one post-dose trough FEV1. This definition describes eligibility for the primary analysis, but the number included in that analysis is not reported in the registry record. The number enrolled does not, by itself, identify the number contributing to the primary endpoint. Nor does the stated set establish how participants with incomplete follow-up were handled after meeting the entry criteria.

In general, an analysis population defines which participants contribute to a particular estimate. Different definitions can lead to different interpretations, especially if participants are excluded after randomization or if endpoint data are incomplete. The record does not report the analysis-population counts by group, reasons for exclusion, or sensitivity analyses addressing alternative population definitions.

What do the design labels establish?

The official title describes a randomized, double-blind, parallel-group trial. Parallel-group means participants are assigned to one treatment group for comparison over the study period, rather than crossing between treatments as part of the stated design. The record does not state the allocation method, and it separately flags that the arms are not a like-for-like control comparison. Details about sequence generation, concealment, blinding procedures, and the basis for the comparison warning are not reported in the registry record. As a result, those design labels do not supply enough information to assess the protection against selection or measurement bias.

How should multiple outcomes be considered?

The record lists 114 outcome measures and 114 analyses, with multiple lung-function outcomes and assessment times. In general, evaluating many outcomes can increase the chance that some appear notable by chance if no adjustment or prespecified hierarchy is used. An analysis plan may address this by designating a primary outcome, controlling a family-wise error rate, or treating secondary analyses as exploratory. Which approach was used, whether multiplicity adjustments were made, and how the many analyses relate to one another are not reported in the registry record. Naming a primary endpoint does not establish the handling of all secondary outcomes.

What can the sample-size illustration say?

In general, a sample-size calculation estimates how many participants would be needed under stated assumptions to detect a target effect with a chosen statistical operating characteristic. The record describes an illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation; the target effect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed using that calculation, and they do not represent observed power. The illustration’s numerical sample-size results are not reported in the registry record. The trial’s own sample-size justification is also not reported in the registry record.

In general, observed power calculated from an observed effect is not a substitute for an effect estimate and confidence interval. Precision is better understood from the uncertainty around the estimated contrast. Because the primary result and its uncertainty are not reported, the precision of the comparative efficacy estimate cannot be assessed. The record also does not report interim analyses, stopping rules, or the statistical plan governing the final analysis.

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", "Combivent (Ipratropium/Albuterol)")
n   <- c(152, 158)
m   <- c(0.081, -0.025)
sp  <- c(0.018, 0.018)
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  152  0.081  0.222  0.045  0.117
CARM  Combivent (Ipratropium/Albuterol)  158  -0.025  0.226  -0.061  0.011

11. Multiplicity, Missing Data and Analysis Populations

The record lists 114 outcome measures and 114 analyses. Several listed measures assess related lung-function concepts at different times, including trough, peak, and average-hourly FEV1, as well as FVC. In general, considering many outcomes creates a multiplicity issue: without a planned approach, the chance of finding an apparently unusual result somewhere among many comparisons can increase. A prespecified primary endpoint can help focus interpretation, but does not explain how secondary outcomes were handled. Whether the trial used multiplicity adjustments, a hierarchy, or exploratory analyses is not reported in the registry record.

The primary analysis population is described as the Full Analysis Set, comprising randomized participants who received study medication and had baseline FEV1 and at least one post-dose trough FEV1. The number in that set and the number analyzed in each group are not reported in the registry record. The record does not explain how missing follow-up measurements were handled, whether any values were imputed, or whether sensitivity analyses were conducted. It also does not report reasons for missing measurements or withdrawals.

In general, missing-data methods rely on assumptions about why measurements are unavailable. Different assumptions can affect estimated group changes, so clear reporting of the method and supporting sensitivity analyses is useful. The eligibility definition for the Full Analysis Set does not reveal what happened to participants lacking later measurements or how incomplete outcome data affected the estimates.

The protocol, prespecified statistical analysis plan, interim analysis procedures, and detailed analysis-population rules are not reported in the registry record. Consequently, it is not possible to assess whether the recorded outcome hierarchy and analysis methods followed a prespecified plan.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 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 (2.3%), death (1.2%), cellulitis (0.6%), basal cell carcinoma (0.6%), squamous cell carcinoma (0.6%).

The registry record reports serious adverse events for 11 of 173 participants in the tiotropium group and 12 of 176 participants in the Combivent group. It reports other adverse events for 11 of 173 participants in the tiotropium group and 9 of 176 participants in the Combivent group. These are participant counts with events and the corresponding numbers at risk as recorded for each group; they are not, by themselves, a test of whether the groups differ.

In general, adverse-event counts describe what was recorded during a study, not whether a treatment caused an event. Interpretation depends on the event definitions, observation period, completeness of reporting, and participant exposure. The registry record does not report the statistical method used to compare these safety figures, detailed event timing, or an adjusted analysis. The number of deaths is not reported in the registry record.

The listed serious-event terms include chronic obstructive pulmonary disease at 2.3%, death at 1.2%, and cellulitis, basal cell carcinoma, squamous cell carcinoma, and convulsion at 0.6% each. These terms and percentages are not accompanied by group attribution in the record. The figures should therefore be read as listed event information, not as evidence of a treatment-specific risk or a causal relationship.

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

The registry record establishes the clinical question, the endpoint definition, the treatment descriptions, and selected safety counts. It does not report the numerical result for the primary endpoint. Without group estimates and a between-group comparison, the direction, size, and precision of the primary effect are unknown from this record. The listed secondary outcomes likewise have no numerical results reported in the registry record.

This absence does not show that the treatments had equal effects, nor does it show that one was better. It means the registry information available for this analysis does not permit a quantitative judgment about comparative lung-function change. In general, a conclusion about an effect should consider its estimate and uncertainty, and should not rest only on whether a statistical test crosses a threshold. Those estimates and tests are not reported in the registry record.

The study is described as a phase 4 parallel-group trial in people with COPD currently prescribed Combivent MDI. The official title calls it randomized and double-blind, but the allocation method is not stated, and the record flags that the arms are not a like-for-like control comparison. Without further detail, the implications of that warning cannot be determined. The treatment schedule and population description also do not establish adherence, protocol deviations, or how treatment exposure was handled in the analysis.

The adverse-event counts can be described as recorded counts, but they do not establish that an event was caused by a treatment. Event definitions, a comparative safety analysis, and death counts are not reported in the registry record. The event-term percentages are not assigned to a treatment group in the record.

Accordingly, the sound interpretation is bounded: the registry describes a study intended to compare two active regimens on lung-function and safety outcomes, but it does not include the primary efficacy results needed to evaluate the comparison. This limitation is about what the record reports, not evidence of a particular clinical outcome.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it asks a comparative question using a continuous lung-function endpoint measured at a specified point in the dosing interval. The endpoint is change from baseline in trough FEV1 at 12 weeks. Continuous measures can be summarized with group means and compared through an estimated difference, while the uncertainty around that difference helps show how precisely the comparison is known.

The registry record names the primary summary as a least-squares mean with standard error, so interpretation depends on more than the endpoint label. The analysis model determines how a least-squares mean is estimated and what adjustments it incorporates. That model is not reported in the registry record. The estimated primary results and their uncertainty are also absent, preventing assessment of either effect size or precision.

The record lists many outcome measures and analyses, which raises the general statistical importance of prespecification and multiplicity management. A primary endpoint helps orient interpretation, while a clear plan for secondary measures reduces the risk of emphasizing results selected after examining the data. The registry record does not report the plan for handling multiple outcomes, missing measurements, or interim analyses.

There is also a design-reporting issue. The official title describes randomization, but the allocation method is not stated; the record additionally notes that the arms are not a like-for-like control comparison. These details matter because statistical interpretation depends on how groups were formed and what differs between them. The record does not explain the warning or the allocation process.

Finally, the safety information illustrates the distinction between event counts and comparative inference. Counts can describe observed events, but they do not establish causation or quantify a treatment contrast without context and analysis. The record’s limited results make transparent reporting of estimates, uncertainty, analysis populations, and safety methods especially important for interpreting this study.

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 main limitation is that numerical efficacy results are not reported in the registry record. The primary endpoint is defined, but group changes, the between-group estimate, its uncertainty, and a p-value are absent. Numerical results for the listed secondary outcomes are also not reported, so the comparative lung-function findings cannot be assessed.

The design information is incomplete for evaluating group comparability. The official title describes randomization and double blinding, but the allocation method is not stated. The record also cautions that the arms are not a like-for-like control comparison, without explaining the basis for that characterization. Further details about randomization, concealment, blinding, deviations, and the nature of the comparison are not reported in the registry record.

The record gives a Full Analysis Set definition but not its size, group-specific analysis counts, or the handling of incomplete endpoint data. Missing-data methods, imputation, sensitivity analyses, and reasons for missingness are not reported. The model used for the least-squares means is likewise not reported, limiting assessment of adjustment and assumptions.

There are 114 outcome measures and 114 analyses, but the registry record does not describe multiplicity control or a detailed prespecified analysis plan. The trial’s own sample-size justification and any interim analysis plan are not reported. Although an illustrative planning approach is described, its numerical results are not reported in the registry record and it is not evidence of the trial’s original design rationale.

Safety reporting is also limited: the record gives participant counts for serious and other adverse events, but not death counts, group attribution for the listed serious-event percentages, or a detailed comparative safety method. These reporting gaps constrain interpretation; they do not establish that an unreported event or analysis did or did not occur.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Trial Comparing Treatment With Tiotropium Inhalation Capsules to Combivent Inhalation Aerosol in COPD Patients. — NCT00359788.
• Registry record last updated 2014-05-16; status last verified 2013-09.
• Results first posted 2009-11-10.
• 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

The registry record describes a completed phase 4, parallel-group study of tiotropium versus Combivent in people with COPD currently prescribed Combivent MDI. Enrollment was 349. The official title describes a randomized, double-blind, 12-week comparison, but the allocation method is not stated. The record also flags that the arms are not a like-for-like control comparison.

The primary endpoint is change from baseline in trough FEV1 at 12 weeks, measured in liters, with trough assessed 10 minutes before drug administration. The stated analysis population is the Full Analysis Set. Numerical primary and secondary efficacy results, the analysis model, missing-data methods, multiplicity procedures, and the trial’s sample-size justification are not reported in the registry record.

Serious and other adverse-event participant counts are recorded for both groups. Death counts are not reported in the registry record. Overall, the record describes the study question and selected design and safety information, but does not report the efficacy results needed to characterize the primary comparison.