Efficacy and Safety of Tiotropium and Salmeterol in Moderate Persistent Asthma Patients Homozygous for B16-Arg/Arg: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Tiotropium and Salmeterol in Moderate Persistent Asthma Patients Homozygous for B16-Arg/Arg (NCT00350207), a registered phase 2 study. The primary outcome is Change in Mean Weekly Morning Peak Expiratory Flow From Baseline to the End of the Trial.

2. Clinical Question

3. Trial Design

This phase 2 study is described as a multicentre, multinational, parallel-group trial in patients with moderate persistent asthma and the B16-Arg/Arg genotype. The registry narrative characterizes it as randomized, double-blind, double-dummy and placebo-controlled. The official title gives a 16-week treatment period. Enrollment was 388, and the recorded status is completed.

Before randomisation, patients entered a 4-week run-in period on salmeterol delivered by metered dose inhaler. During the 16-week treatment period, the study groups received tiotropium once daily, salmeterol twice daily, or placebo twice daily. After that period, the brief summary says all patients received salmeterol twice daily for four weeks. The official title specifies the stated inhaler and dose schedules for tiotropium and salmeterol.

Patients recorded morning and evening PEF and FEV1 daily using an electronic peak flow meter. The electronic diary also recorded asthma control and rescue-medication use. At study visits, the Mini-Asthma Quality of Life Questionnaire was administered, and pulse, blood pressure, and pre-dose pulmonary function, including FEV1 and forced vital capacity, were assessed. The registry lists 63 outcome measures and eight secondary outcomes, all of which concern mean weekly morning or evening PEF at specified visits.

The study description states that treatment was randomized, but allocation details are not reported in the registry record. The record does not report the statistical analysis plan, sample-size justification, interim analyses, or results for the primary endpoint. Consequently, the design and measurement schedule are described more fully than the analytic details or efficacy findings.

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 Full analysis set (FAS) included patients who received at least one dose of randomised study medication and who had at least four patient diary records for at least one efficacy endpoint in any week after the first administration of the randomised treatment and baseline data for the corresponding efficacy endpoint.

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 includes all patients who were dispensed randomised study medication and were documented to have taken at least one dose of investigational treatment.

6. Primary Endpoint

The registry lists the primary outcome as Change in Mean Weekly Morning Peak Expiratory Flow From Baseline to the End of the Trial, measured over baseline and after 16 weeks of treatment.

The primary endpoint is change from baseline in mean weekly morning peak expiratory flow at the end of the 16-week treatment period. PEF is a measure of how quickly a person can force air out of the lungs. The endpoint summarizes morning readings over a week rather than relying on a single measurement. The registry defines baseline as the last week before the randomisation visit, and gives the measurement unit as L/min.

Change from baseline expresses how the measurement at follow-up differs from its starting value. This can help describe the course of lung function during the treatment period while accounting for the level recorded before randomisation. The endpoint is continuous: it can take a range of measured values rather than representing a yes-or-no event. The registry identifies the reported summary as a least-squares mean and the dispersion measure as a standard error.

Repeated diary measurements can capture day-to-day variation and support a weekly average. Morning readings are the designated primary outcome; evening readings and later weekly measurements are listed among the secondary outcomes. The registry record does not report the primary endpoint estimates, the comparison estimates, or their uncertainty. Thus, the endpoint’s definition and measurement schedule are available, but its observed result cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean represent?

In general, a least-squares mean is an estimate obtained from a statistical model rather than simply the arithmetic average of the observed values. A model can account for specified features of the data, such as baseline measurements or study groups, when estimating group outcomes. The exact model and the terms included in it are not reported in the registry record, so the adjustment behind the named least-squares mean cannot be reconstructed from the endpoint description alone.

For a continuous outcome such as PEF, a group estimate describes the outcome on its measurement scale. A comparison between groups would usually express how their estimated changes differ, alongside an uncertainty measure. The registry record does not report a primary endpoint comparison, so there is no posted estimate to interpret in terms of direction or size.

How should the standard error be understood?

In general, a standard error describes the statistical uncertainty in an estimated quantity, such as a mean. It reflects how much the estimate would be expected to vary across repeated samples under the assumptions of the analysis. It is not the same as the spread of individual participants’ measurements. A standard error can contribute to a confidence interval, which gives a range of values compatible with the data and the model at a stated confidence level.

The endpoint description names standard error as the dispersion measure, but no primary estimate or standard error is reported. A reader therefore cannot assess how precisely the mean change was estimated. Nor can a confidence interval or a test result be recovered from the endpoint description.

Why do repeated measurements matter?

Daily diary readings provide repeated observations for each participant. Averaging readings over a week can reduce the influence of a single unusually high or low measurement, while retaining a measure of the participant’s lung function over that period. Repeated measurements also create analytic choices: a model might use all available readings, form weekly summaries, or account for correlations among measurements from the same person. The record identifies the weekly endpoint and diary schedule, but does not explain which modeling approach was used for the repeated data.

In general, observations from the same participant tend to be related rather than independent. Statistical methods can account for that relationship, but the particular method and its assumptions are not reported in the registry record. It is therefore not possible to assess the model’s handling of within-participant correlation.

What does a planning illustration tell readers?

The registry record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes planning for different fractions of that observed effect. Such figures are hypothetical planning scenarios: they indicate the number of participants per arm that a calculation would require under its stated assumptions. They are not the number of participants actually observed, and they are not observed power.

Because the illustration is based on an observed effect, it should not be treated as the trial’s original sample-size justification. The protocol’s sample-size justification is not reported in the registry record. The record does not report the numerical planning outputs in the study information, so none can be interpreted or repeated.

What statistical details remain unknown?

The record does not report the analysis model, the treatment contrast specification, the handling of missing endpoint data, or the assumptions used to assess model fit. It does not report whether analyses were adjusted for baseline PEF or other characteristics, whether any subgroup analyses were planned, or whether interim analyses were conducted. These details matter because analytic choices can affect estimates and their uncertainty. Their absence does not establish that a particular method was or was not used; it means the method is not reported in the registry record.

The registry lists multiple outcomes and follow-up times. In general, testing many outcomes can increase the chance of observing a nominally unusual result even when there is no underlying effect. Statistical plans may address this through a prespecified hierarchy or other multiplicity procedures. No such procedure is reported, and the record does not post the outcome tests needed to examine how multiplicity was handled.

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", "Salmeterol", "Placebo")
n   <- c(128, 134, 125)
m   <- c(-3.93, -3.15, -24.63)
sp  <- c(4.873, 4.64, 4.835)
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  128  -3.930  55.132  -13.573  5.713
CARM  Salmeterol  134  -3.150  53.712  -12.328  6.028
CARM  Placebo  125  -24.630  54.057  -34.200  -15.060

11. Multiplicity, Missing Data and Analysis Populations

The record lists 63 outcome measures. Its secondary outcomes include mean weekly morning PEF and mean weekly evening PEF at weeks 4, 8, 12 and 16. Multiple outcomes and time points raise the general issue of multiplicity: when many statistical tests are performed, the chance of at least one apparently unusual result can increase. A prespecified testing hierarchy or adjustment procedure can help control that issue. Whether this trial used such an approach is not reported in the registry record.

No primary or secondary endpoint estimates or p-values are reported, and the registry lists no analyses. Consequently, the posted information does not allow readers to check which outcomes were analyzed, whether the primary outcome was tested as planned, or whether any multiplicity method was applied. Interim analyses are also not reported in the registry record.

The primary endpoint population is described as the Full analysis set. It included patients who received at least one dose of randomized medication, had at least four diary records for at least one efficacy endpoint in a post-treatment week, and had baseline data for the corresponding endpoint. The population description is truncated after this eligibility detail. The record does not report the number included in the primary analysis or explain how participants who did not meet the criteria were handled.

Missing-data methods are not reported in the registry record. In general, missing measurements can affect an estimate if the participants with observed data differ systematically from those without measurements. The method used to address missing diary entries or other unavailable outcomes, and the assumptions that method would require, cannot be determined from the registry information.

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: asthma (3.0%), abdominal pain upper (0.8%), meningitis (0.8%), pilonidal cyst (0.8%), nausea (0.7%).

The registry reports serious adverse events affecting 2 of 128 participants in the tiotropium group, 7 of 134 in the salmeterol group, and 1 of 126 in the placebo group. It also reports other adverse events affecting 21 of 128, 18 of 134, and 25 of 126 participants, respectively. These are counts of participants affected as recorded in the registry; they do not provide event-level detail for every participant or establish the cause of an event.

The listed serious adverse event terms include Asthma at 3.0%, Abdominal pain upper at 0.8%, Meningitis at 0.8%, Pilonidal cyst at 0.8%, Nausea at 0.7%, and Gastroenteritis at 0.7%. These terms and percentages are presented as registry safety information; they should not be assumed to describe all events or to indicate that an event was caused by a study treatment.

Deaths are not reported in the registry record. The event counts are descriptive and do not establish a comparative safety effect. Differences in counts alone do not account for uncertainty, event severity beyond the registry classification, exposure time, or other aspects of safety analysis.

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

This trial record identifies a specific population, treatment schedule, and primary lung-function outcome. It describes a phase 2 parallel-group study in patients with moderate persistent asthma who had the B16-Arg/Arg genotype. The primary outcome was change in mean weekly morning PEF from baseline to 16 weeks, measured in L/min.

What the record does not provide is equally important: it contains no reported primary endpoint estimates, between-group comparison, confidence interval, standard error for a treatment contrast, or p-value. It therefore does not show how much the groups changed, whether their changes differed, or how precisely any difference was estimated. The absence of a posted result is not evidence that there was no effect; it leaves the effect unquantified in this record.

The study narrative describes randomisation and blinding, but allocation details and the statistical analysis plan are not reported. The registry also does not report the primary analysis sample size or missing-data methods. Those omissions limit assessment of how the planned comparison was implemented and how robust any analysis might be.

The safety counts provide descriptive information about recorded adverse events in the three groups. They are not a substitute for the missing efficacy analysis and should not be used to infer the comparative effect on PEF. Nor do the counts alone establish whether treatment caused an event or whether the groups differed in safety.

Accordingly, the defensible interpretation is limited to the trial’s stated objective, design, endpoint, and recorded safety summaries. Conclusions about efficacy, statistical significance, clinical importance, or comparative safety require results and analytic details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a defined genotype-based population with a continuous, repeatedly measured lung-function endpoint. Restricting the target population to patients homozygous for B16-Arg/Arg makes the question specific to that group. It also means that the record alone cannot establish whether findings would apply to people with other genotypes or to other asthma populations.

Daily morning and evening PEF measurements create a rich measurement schedule, while also requiring clear decisions about summarizing repeated readings, handling missing diary entries, and accounting for within-participant correlation. The registry describes weekly mean PEF outcomes at several follow-up times, but does not report the statistical methods used to analyze them. The distinction between a clearly defined endpoint and a fully reported analysis is important: the former does not by itself reveal the estimated treatment effect or its precision.

The record also illustrates why a trial’s design description and its results must be read separately. It describes randomisation, blinding, three treatment arms, and a 16-week treatment period. Yet it does not post the primary efficacy estimates or analyses. Without those results, readers cannot evaluate the magnitude, uncertainty, or statistical significance of the intended comparison.

Finally, the registry’s planning illustration is explicitly based on an observed effect and stated assumptions. It can be understood as a hypothetical sample-size planning exercise, not as a report of observed power and not as evidence about the treatment effect. The distinction helps prevent planning calculations from being mistaken for trial findings.

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 for statistical interpretation is that the registry record does not report the primary efficacy results. There are no group-level changes, treatment contrasts, confidence intervals, standard errors for comparisons, or p-values. Without these, neither the size nor the precision of the primary result can be evaluated.

The analysis model and its assumptions are not reported. Although the outcome is identified as a least-squares mean, the model terms and any adjustment are unspecified. The record also does not describe handling of missing diary data, the number of participants included in the primary analysis, or the extent of missingness. The Full analysis set criteria are described only in part.

Allocation details are not reported, despite the study narrative describing randomisation. The registry record does not provide the statistical analysis plan, a sample-size justification, interim-analysis information, or a multiplicity strategy. The presence of numerous listed outcomes makes the absence of a reported testing approach relevant to interpreting any results, were they available.

The safety information is limited to group counts and selected serious adverse event terms. Deaths are not reported in the registry record, and the available summaries do not establish causality or provide a complete comparative safety analysis. These limitations concern what the registry record reports; they do not establish that the underlying study did not collect or analyze additional information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety of Tiotropium and Salmeterol in Moderate Persistent Asthma Patients Homozygous for B16-Arg/Arg — NCT00350207.
• Registry record last updated 2013-12-24; status last verified 2013-09.
• Results first posted 2009-11-17.
• 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 2, parallel-group study sponsored by Boehringer Ingelheim, with enrollment of 388. It concerns tiotropium, salmeterol, and placebo in patients with moderate persistent asthma and the B16-Arg/Arg genotype. The study narrative describes a 4-week salmeterol run-in, a 16-week treatment period, and a subsequent four-week period on salmeterol for all patients.

The primary endpoint was change from baseline in mean weekly morning PEF at 16 weeks, summarized as a least-squares mean with standard error. The record does not report primary efficacy estimates or analyses. It lists secondary PEF outcomes and provides descriptive adverse event counts by group. Analysis methods, missing-data handling, multiplicity procedures, allocation details, and the protocol’s sample-size justification are not reported in the registry record.