Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Combination of GSK573719 and GW642444 in Subjects With COPD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Combination of GSK573719 and GW642444 in Subjects With COPD (NCT01039675), a randomized phase 2 study. The primary outcome is Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28.

2. Clinical Question

3. Trial Design

This phase 2 study was randomized, double-blind, and parallel-group, and is recorded as completed. It evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of a combination of GSK573719 and GW642444 compared with placebo in people with COPD. The enrollment recorded for the study is 51. The registry record lists a start date of 2010-01-01 and a primary completion date of 2010-04-01.

The intervention is listed as 500mcg/25mcg once daily, while the active arm is titled UMEC/VI 500/25 µg QD. The comparator is placebo once daily. The record does not provide arm descriptions beyond those names, so details such as treatment delivery procedures and adherence are not reported in the registry record.

The primary endpoint was change from baseline in weighted mean pulse rate at Day 28. Two secondary outcomes concern change from baseline in weighted mean pulse rate over 0 to 6 hours post-dose at Day 1 and Day 14, and change from baseline in maximum and minimum pulse rate over 0 to 6 hours post-dose on Days 1, 14, and 28. The registry lists three outcome measures and one analysis. It does not report a fuller account of the protocol’s statistical design, a sample-size justification, or the basis for choosing the enrollment target.

The primary analysis is described as using a repeated measures model, with baseline pulse rate, sex, age, smoking status, treatment, day, day by treatment, and day by baseline interactions as covariates. The registry record does not give the model’s detailed specification or explain how the reported final-values contrast relates to that model. Further details about allocation concealment and masking procedures are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants (par.) who met eligibility criteria at Screening (Visit 1) completed a 5- to 8-day Run-in period and were then randomized to a 4-week treatment period. A total of 77 par. were screened; 52 par. were randomized and 51 par. received at least one dose of study drug (one par. was randomized in error but did not receive study drug).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received \>= 1 dose of randomized study medication. All participants with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 28.

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 Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28, measured over Baseline and Day 28.

The primary endpoint is change from baseline in weighted mean pulse rate over 0 to 6 hours post-dose at Day 28, measured in beats per minute. Pulse rate is the number of heartbeats in a minute. The weighted mean is calculated from the area under the pulse-rate/time curve divided by the time interval over which the area is calculated. For this endpoint, the Day 28 measurements include pre-dose and post-dose measurements at 15 minutes, 45 minutes, 1.5 hours, 3 hours, and 6 hours.

Baseline is defined as the most recent pulse-rate result taken on or before pre-dose Day 1. Change from baseline is defined as the Day 28 weighted mean minus that baseline value. Using multiple measurements across the post-dose interval provides a summary of pulse rate over time rather than relying on a single reading. As a general statistical point, such a summary can represent the pattern across the measurement window, while still depending on the timing and completeness of measurements.

The registry reports least-squares means with standard errors for the treatment arms. The study’s primary analysis description names a repeated measures model and lists baseline and participant characteristics among its covariates. However, the registry record does not report the full model specification or explain the relationship between that model and the reported mean difference in final values.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record gives several different statistical descriptions that answer related but distinct questions. The primary outcome is a continuous measure: change in weighted mean pulse rate from baseline. A continuous measure can take values across a scale, rather than being a count of events or a yes-or-no outcome. For a continuous outcome, an arm mean describes the central location of observed or modeled measurements, while a standard error describes the uncertainty in an estimated mean. A standard error is not a description of the spread of individual participant values; that is a different statistical quantity.

What does the repeated measures description mean?

The primary analysis is described as a repeated measures model. In general, repeated measures methods account for multiple observations taken from the same participant, which are usually related rather than independent. Using measurements across time can help estimate patterns over the measurement occasions while accounting for that within-participant structure. The registry lists baseline pulse rate, sex, age, smoking status, treatment, day, day by treatment, and day by baseline interactions as covariates. It does not report the model’s exact covariance structure, estimation method, handling of incomplete repeated measurements, or other implementation details. Those elements are not reported in the registry record.

The terms day by treatment and day by baseline indicate that the described model includes interactions involving day and treatment, and day and baseline. In general, an interaction allows the association between one model term and the outcome to vary across levels of another term. The record does not give coefficient estimates for these terms or describe how the final contrast was derived from them. Thus, the listed model terms provide a partial account of the analysis, not a complete specification.

How should the means and contrast be read?

The treatment-arm results are reported as least-squares means with standard errors. In general, a least-squares mean is a model-based mean, often adjusted for terms included in a statistical model. The registry does not fully state which model produced these particular arm summaries. The separate contrast is labeled Mean Difference (Final Values), and its estimate is -0.5 with a 95% confidence interval from -5.5 to 4.5. The registry does not name the method used to calculate this contrast, and the method field is not reported in the registry record.

A confidence interval expresses uncertainty around an estimate under the assumptions of the calculation. A 95% confidence interval is conventionally interpreted through the long-run performance of the interval procedure: across repeated applications under the same conditions, the procedure would cover the target quantity at the stated rate. It is not a statement that there is a 95% probability that this particular interval contains the true value. The interval’s span also makes clear that the point estimate alone is not an adequate description of precision.

What does a recalculation add?

A recalculation based on posted summary statistics is generally an unadjusted check, not a replacement for the trial’s prespecified or sponsor-reported analysis. For this continuous endpoint, the registry record indicates that values are missing or not estimable for a two-arm comparison. Consequently, no recalculated two-arm estimate is available to compare with the reported contrast. The arm summaries should not be used to invent a contrast or to infer a p-value. The sponsor’s reported analysis remains the available direct comparison, while its method details are not reported in the registry record.

What can sample-size planning illustrations establish?

In general, sample-size calculations illustrate how a future study’s planned size may relate to assumptions about an effect, variability, allocation, and a chosen significance level and power. The planning assumptions recorded for this study’s illustrations use a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as stated fractions of the observed effect. Such planning illustrations are not the observed power of the completed trial and do not show what its statistical power was. Numerical planning results are not included in the registry record for this explanation, and the trial’s own design assumptions or sample-size justification are not reported in the registry record.

Statistical significance and precision are also distinct concepts. A p-value, if reported, would summarize how unusual the observed data or more extreme data would be under a specified null model and its assumptions. The registry does not report a p-value for this contrast. A confidence interval instead presents a range of estimates, and its width is relevant to precision. Neither measure alone establishes clinical importance; the registry record does not provide an interpretation threshold for the pulse-rate outcome.

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("Placebo", "UMEC/VI 500/25 µg QD")
n   <- c(9, 35)
m   <- c(1.4, 0.9)
sp  <- c(2.2, 1.05)
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  Placebo  9  1.400  6.600  -3.673  6.473
CARM  UMEC/VI 500/25 µg QD  35  0.900  6.212  -1.234  3.034

11. Analyses Reported by the Sponsor

The registry’s reported comparison is a mean difference in final values of -0.5, with a 95% confidence interval from -5.5 to 4.5. Its method is not specified, and a p-value is not reported. The primary outcome description separately states that analysis was performed using a repeated measures model with listed covariates, but the record does not clarify whether that model produced the reported contrast.

No recalculated two-arm contrast is available for this continuous outcome because the values are described as missing or not estimable for that comparison. As a result, there is no recalculated estimate to place alongside the sponsor-reported estimate or to use as an independent check. The displayed arm summaries do not substitute for a recalculated contrast.

The registry records no discrepancy between a recalculation and the sponsor’s analysis. Since no recalculated contrast is available, that status should not be read as evidence that an independent numerical comparison confirmed the sponsor’s result. The sponsor-reported contrast is the available direct estimate; the information needed to reproduce its calculation is not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures, including the primary pulse-rate outcome and two secondary pulse-rate outcomes. The secondary outcomes concern change from baseline in weighted mean pulse rate over 0 to 6 hours post-dose at Day 1 and Day 14, and change from baseline in maximum and minimum pulse rate over 0 to 6 hours post-dose on Days 1, 14, and 28. The record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or an analysis plan describing how multiple comparisons were handled. Those details are not reported in the registry record.

As a general statistical consideration, examining multiple outcomes or time points can increase the chance of obtaining an apparently notable result by chance if each is assessed separately. Prespecification and a stated testing strategy help readers understand how to interpret a family of results. Without such information, the posted primary contrast can be described on its own terms, but the wider set of outcome assessments cannot be interpreted as a controlled set of confirmatory tests.

The primary analysis population is described as randomized participants who received at least one dose of randomized study medication and had at least one post-baseline assessment and non-missing covariate data. The arm counts reported for the primary endpoint are 9 for placebo and 35 for UMEC/VI 500/25 µg QD. The enrollment recorded for the study is 51. The registry record does not explain the relationship among enrollment, the treated population, and the participants included in the primary analysis, or why the listed analysis counts differ from enrollment.

The registry does not report how missing outcome data were handled, whether any imputation was used, or whether sensitivity analyses assessed the effect of missing data. It also does not provide a complete account of exclusions from the primary analysis. These gaps matter because an analysis limited to participants with post-baseline measurements and non-missing covariates may not represent every randomized participant. The magnitude or direction of any resulting influence cannot be determined from the registry record.

13. 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 3% reporting threshold.

Most frequent non-serious adverse event terms

The safety figures list serious adverse events for 0 of 9 participants at risk in the placebo group and 0 of 42 participants at risk in the UMEC/VI 500/25 µg QD group. For other adverse events, the record lists 1 of 9 at risk in the placebo group and 1 of 42 at risk in the active group. Death counts are not reported in the registry record.

These counts describe the entries recorded for the stated groups and denominators. They are not the same population counts as the primary-endpoint analysis, which lists 9 participants for placebo and 35 for the active arm. The registry does not explain the difference between the safety denominators and the primary-analysis counts. The serious-event terminology list is empty in the record.

As a general statistical point, a small number of observed events gives limited information about how often an event might occur in a broader population. Counts alone also do not establish whether an event was caused by study treatment. The registry record does not report event-specific details, follow-up completeness, or a causal assessment in the registry record. These figures should therefore be read narrowly as the posted safety counts, not as proof that serious events did or did not occur outside the recorded observations.

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

The primary result describes a comparison of change in weighted mean pulse rate at Day 28 between the combination and placebo groups. The reported mean difference in final values is -0.5, and the associated 95% confidence interval ranges from -5.5 to 4.5. The interval crosses zero, and it spans values on both sides of the point estimate. This indicates that the posted estimate is not precise enough to confine the comparison to one side of zero under the stated interval method.

That statistical description does not determine whether the endpoint difference is clinically important. The registry record does not report a threshold for a meaningful change in pulse rate, nor does it report a prespecified non-inferiority or equivalence margin. Although the analysis type is labeled non-inferiority or equivalence, that label alone does not establish the study’s decision criterion or demonstrate that a criterion was met. No such margin or conclusion is reported in the registry record.

The primary endpoint is a physiological measure collected over a defined post-dose window. It is not, by itself, a complete assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, or COPD outcomes. The study summary names those broader areas, but the registry entries do not contain numerical results for all of them. The pulse-rate finding should not be generalized beyond what it measures.

The registry reports a relatively small enrollment and provides smaller arm-specific counts for the primary analysis. It does not explain the participant flow into the analysis or the handling of missing data. Along with the wide confidence interval and limited reporting of the contrast method, this means readers have important uncertainty about both precision and analytic details.

The result is a record of the posted study estimate, not a recommendation about treatment. It neither establishes a clinically meaningful difference nor rules one out on the basis of the information reported. Interpretation is limited to the endpoint, comparison, analysis population, and follow-up information documented in the registry record.

15. Why This Trial Matters Statistically

This study is statistically informative as an example of the difference between an endpoint’s definition, an arm-level summary, and a treatment contrast. The primary outcome is defined using repeated pulse-rate measurements over a post-dose interval, while the results include least-squares means with standard errors and a separately labeled mean difference in final values. Keeping those quantities distinct prevents an arm summary from being mistaken for the direct comparison of interest.

The record also illustrates why model descriptions and results need to be read together. A repeated measures model is identified, and its covariates are listed, but the reported contrast method is not specified. Without the link between the model and the contrast, readers cannot fully reproduce or assess the reported estimate. This is not a reason to replace the posted result with an improvised calculation; rather, it marks a limit on independent verification.

Precision is central to interpreting the contrast. The reported confidence interval extends across zero, and its width shows that the result allows a range of possible values. The point estimate alone would conceal that uncertainty. The record does not provide a clinical interpretation threshold, so statistical uncertainty cannot be translated into a judgment about practical importance from these registry entries alone.

The study’s outcome list and analysis-population description also raise general questions about multiplicity and missing data. The registry does not report a testing strategy for its outcomes or the handling of missing observations. Those omissions make it harder to assess how the primary result fits within the broader analysis and whether the analyzed participants fully represent those randomized and treated.

Finally, the safety counts demonstrate why denominators and outcomes must be read precisely. The safety group counts are not the same as the primary-analysis counts, and the record does not explain the difference. Together, these features make the trial a useful case for distinguishing what a registry estimate says from what incomplete reporting leaves unresolved.

16. 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 reported contrast is not accompanied by a stated statistical method or p-value. Although the primary outcome description names a repeated measures model and lists covariates, the record does not say whether the contrast was generated by that model or explain its calculation. This limits reproducibility and makes it difficult to assess the adjustment represented by the reported mean difference.

The arm-level least-squares means and standard errors do not permit a direct recalculation of the contrast from the information available. The registry identifies the two-arm recalculation as missing or not estimable. Consequently, no independent unadjusted estimate is available for comparison with the reported result. The registry also does not state a non-inferiority or equivalence margin, despite labeling the analysis as non-inferiority or equivalence.

The primary-analysis population requires at least one post-baseline assessment and non-missing covariate data. The record does not explain how many randomized participants were excluded, why the primary-analysis counts differ from enrollment, or how missing measurements were handled. No sensitivity analysis for missing data is reported in the registry record.

The record lists secondary outcomes and outcome measures but does not report a multiplicity strategy. It does not provide a detailed protocol or statistical analysis plan, sample-size justification, or fuller explanation of the design assumptions. These omissions limit assessment of prespecification and the role of the primary outcome within the full analysis.

Safety figures are reported with denominators different from the primary analysis, and the record does not explain that difference. Death counts are not reported in the registry record. The registry entries also do not provide numerical results for the full set of pharmacokinetic and pharmacodynamic outcomes named in the study summary. These limitations constrain conclusions to the specific posted pulse-rate and adverse-event information.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Combination of GSK573719 and GW642444 in Subjects With COPD — NCT01039675.
• Registry record last updated 2017-11-08; status last verified 2017-10.
• Results first posted 2014-02-10.
• 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.

20. Record Summary

The registry identifies NCT01039675 as a completed phase 2 randomized, double-blind, parallel-group study in people with COPD. It evaluated GSK573719/GW642444, listed at 500mcg/25mcg once daily, against placebo once daily. Enrollment is recorded as 51.

The primary outcome is change from baseline in weighted mean pulse rate over 0 to 6 hours post-dose at Day 28. The arm summaries are least-squares means with standard errors. The reported mean difference in final values is -0.5, with a 95% confidence interval from -5.5 to 4.5; no p-value is reported. A recalculated two-arm contrast is not available.

The primary analysis is described as a repeated measures model, but the reported contrast method and several analysis details are not reported in the registry record. The safety entries list 0 serious adverse events in each group and 1 other adverse event in each group, with the recorded denominators differing from the primary-analysis counts. These findings should be interpreted within the limits of the registry’s reporting.