A Study of the Efficacy and Safety of Vibegron (MK-4618) in Participants With Overactive Bladder (OAB) (MK-4618-008): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Efficacy and Safety of Vibegron (MK-4618) in Participants With Overactive Bladder (OAB) (MK-4618-008) (NCT01314872), a randomized phase 2 study. The primary outcome is Base Study/Part 1: Change From Baseline in Average Daily Micturitions at Week 8.

2. Clinical Question

The study asked whether vibegron reduced the average daily number of micturitions in participants with overactive bladder, compared with placebo, after 8 weeks of treatment. The registry describes this as the primary hypothesis for the base study. It also included tolterodine ER as an active comparator and evaluated additional treatment groups, including a combination regimen.

This is a question about a diary-based frequency measure over a specified treatment period. It is not, by itself, a complete assessment of overactive bladder symptoms, longer-term outcomes, or the balance of benefits and harms. The registry also lists incontinence and strong-urge outcomes, as well as outcomes during the extension, but these are not the primary endpoint considered in the main comparison.

3. Trial Design

The registry describes a Phase IIb, randomized, double-masked, parallel-group study of vibegron in participants with overactive bladder. Its official title describes a placebo- and active-comparator-controlled study with a 52-week extension. The study status is completed, and the registry records enrollment of 1395. The registry lists a start date of 2011-03-31 and a primary completion date of 2012-10-22.

The base study had two parts. Part 1 included placebo, four vibegron dose groups, tolterodine ER 4 mg, and a group receiving vibegron with tolterodine ER followed by vibegron alone. The Part 1 regimens were described as daily oral treatment for 8 weeks. The primary endpoint was assessed at Week 8. Part 2 included placebo, vibegron 100 mg, tolterodine ER 4 mg, and their combination; the listed Part 2 regimens were for 4 weeks. The extension is described as 52 weeks in the official title, with groups receiving vibegron, tolterodine ER, or their combination. Some extension assignments depended on earlier treatment, as described in the registry.

The primary hypothesis concerned a dose-related change in average daily micturitions with vibegron compared with placebo after 8 weeks. The reported primary outcome is for Base Study/Part 1. The registry’s analysis population is the full analysis set: randomized participants who received at least one dose and had baseline data or at least one post-randomization observation for the endpoint.

Randomization, masking, the parallel-group model, treatment descriptions, and the endpoint population are reported. The registry record does not report the randomization procedure, allocation concealment details, the practical masking procedures, or the planned allocation ratio. It also does not report a sample-size justification in the information summarized for this analysis. Those design details should not be inferred from the enrollment figure or the observed group sizes.

4. Participant Flow and Accounting

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

Before assignment: This was a 2-Part, randomized, double blind placebo- and active-controlled, parallel-group study of vibegron in men and women with Overactive Bladder (OAB). Participants who enrolled in Part 1 were not eligible to participate in Part 2. Participants who completed Part 1 or Part 2 were eligible to enroll in an optional 1-year safety extension.

Only the first 6 of 15 groups are shown.

Treatment Period 1

Reasons for not completing this period:

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set population included all randomized participants who received at least one dose of study treatment and have either baseline data or at least one post-randomization observation for the analysis 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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Base Study/Part 1: Change From Baseline in Average Daily Micturitions at Week 8, measured over Baseline and Week 8.

The primary endpoint was change from baseline in average daily micturitions at Week 8, measured in micturitions. Participants recorded each micturition in a voiding diary. The average daily value was calculated from the total number of micturitions over a week of diary recording, divided by the number of days for which the diary was kept. During the base study, the diary covered 4 to 10 days.

Baseline was defined using the average daily number of micturitions during the week of placebo run-in before the Week 0 visit. The endpoint therefore compares a participant’s diary-based frequency at follow-up with this baseline measure. A negative change indicates a lower recorded average daily number at follow-up than at baseline; it does not, on its own, describe every aspect of symptom experience.

Daily micturition frequency is used because it converts repeated diary observations into a continuous measure that can be compared across treatment groups. A continuous endpoint can retain information about the amount of change rather than reducing each participant’s outcome to a yes-or-no category. The reported group summaries are least-squares means with 95% confidence intervals, rather than raw group means with a standard deviation.

Diary-derived measures depend on recording and on the days available for calculation. The registry record explains the diary calculation, but does not report how incomplete diaries were handled, how many diary days were required for an endpoint value, or how missing follow-up measurements were treated. These details matter when assessing how representative the endpoint estimates are of all randomized participants.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a numerical measure of average daily micturitions. The registry reports least-squares means for the treatment groups and 95% confidence intervals. A least-squares mean is a model-based estimate of a group average. It can differ from a simple arithmetic mean when an analysis accounts for repeated observations or other terms in its model. The registry identifies the reported method for the between-group analyses as constrained longitudinal data analysis, but does not give enough detail in this record to reconstruct every model term or assumption.

What does a confidence interval describe?

A confidence interval represents uncertainty in an estimated quantity under the statistical model and its assumptions. A narrower interval indicates greater precision than a wider interval on the same scale. It does not show the range of outcomes experienced by most participants, and it does not assign a probability to the true effect after the interval has been calculated. For a treatment contrast, an interval that includes zero is compatible with no difference as well as with differences in either direction at the stated confidence level. An interval that excludes zero indicates that zero is not among the values in that interval; interpretation still depends on the analysis plan, data quality, and multiplicity.

For this endpoint, lower values represent fewer average daily micturitions, and changes are recorded as treatment-period values relative to baseline. The registry’s sponsor contrasts are reported as differences in least-squares means. Their negative signs indicate the direction of the estimated contrast as ordered in the reported comparison. The confidence interval gives a range of values consistent with the analysis at the stated confidence level, rather than a guarantee about the true effect.

What is constrained longitudinal data analysis?

In general, longitudinal analysis models measurements collected over time and can use information from more than one time point. A constrained longitudinal approach commonly models the outcome across scheduled measurement occasions while imposing a baseline constraint shared across randomized groups. The approach can estimate treatment-group differences at follow-up while incorporating the longitudinal structure. The registry names this method for the sponsor’s comparisons, but does not report its full specification, including all covariance choices, model terms, or the exact handling of incomplete measurements. Those details should not be assumed.

Model-based analyses rely on assumptions about the outcome data and their relationship over time. The validity of standard errors and confidence intervals can depend on the model specification and the adequacy of its assumptions. The registry record does not provide diagnostics or sensitivity analyses that would allow those assumptions to be assessed from the posted results alone.

How do the arm estimates differ from the contrasts?

The arm estimates describe change from baseline within each group. For example, the placebo arm’s least-squares mean change is -1.16, while the vibegron 100 mg arm’s estimate is -2.07. Those values do not themselves constitute the sponsor’s adjusted comparison. The reported contrast is the model-based difference between groups and is the more direct result for the placebo-controlled question. It is important not to subtract the displayed arm estimates and treat the result as the sponsor’s adjusted estimate: the contrast comes from the sponsor’s longitudinal analysis.

The group-specific confidence intervals also are not a replacement for a confidence interval around a treatment contrast. Whether two group estimates differ cannot be reliably determined merely by looking at whether their separate intervals overlap. The sponsor’s reported contrast and its own interval directly address the estimated comparison.

Why does the analysis population matter?

The registry defines the full analysis set as randomized participants who received at least one dose and had baseline data or at least one post-randomization observation for the endpoint. This is not an all-randomized population as described in some intention-to-treat analyses, because the stated definition includes post-randomization treatment and data criteria. The reported group sizes for the endpoint differ across arms, and safety denominators can differ from endpoint analysis counts. Those differences should not be silently reconciled or treated as evidence about why participants were absent from a particular analysis.

The analysis population definition helps identify which participants could contribute to the endpoint analysis, but does not tell how many were excluded for each criterion or how missing observations were handled. The registry record does not report those details. A complete assessment of the potential impact of missing data would ordinarily consider the amount and pattern of missingness, reasons for missingness, and sensitivity analyses under alternative assumptions. These are not reported in the registry record.

What can planning calculations say?

Sample-size calculations are planning illustrations, not observed power. The stated assumptions for the planning illustration are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. Such calculations show how required sample size depends on chosen assumptions and a target effect. They do not demonstrate that the completed study had a particular probability of finding an effect, and they are not a replacement for the trial’s original design rationale. The registry record does not report the trial’s sample-size justification or enough information to establish that these illustration assumptions were used in the original design.

For non-time-to-event outcomes, the planning convention is participants per arm. The record also states that time-to-event planning tables use total events, but the primary endpoint is continuous. No planning value needs to be interpreted as an observed trial result. A planning estimate does not change the uncertainty expressed by the actual confidence intervals or address multiplicity and missing data.

10. Analyses Reported by the Sponsor

The sponsor’s own analysis is the primary source for interpreting the reported treatment contrasts. It used constrained longitudinal data analysis and reports differences in least-squares means, 95% confidence intervals, and p-values for comparisons with placebo and tolterodine ER. No discrepancy between a recalculation and the sponsor’s analysis is flagged in the registry information for this result. There is therefore no indicated conflict requiring a recalculation to replace the sponsor’s reported estimate.

The sponsor reports placebo comparisons for vibegron 3 mg, 15 mg, 50 mg, and 100 mg, and a comparison of tolterodine ER 4 mg with placebo. The corresponding p-values are 0.056, 0.064, 0.007, < 0.001, and 0.026, respectively. The estimates and their confidence intervals should be read together: the 3 mg and 15 mg intervals include zero, while the intervals for 50 mg, 100 mg, and tolterodine ER exclude zero. The registry record does not report adjustment for multiple comparisons, so these p-values should not automatically be treated as multiplicity-adjusted evidence.

The posted arm means are useful for describing the observed pattern of estimated within-group change, but they do not provide an independent replication of the sponsor’s model-based contrasts. The registry record does not report a recalculated contrast to compare with the sponsor’s result. Nor does it report enough model detail for an independent reconstruction of constrained longitudinal data analysis. The sponsor’s reported model analysis should therefore anchor interpretation of the treatment comparisons, with the limits of the available reporting kept in view.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several Part 1 treatment groups and reports multiple comparisons for the primary endpoint. It reports placebo comparisons for four vibegron doses and tolterodine ER 4 mg. The primary hypothesis is described as dose-related, but the registry record does not report a dose-trend test or a multiplicity strategy for the reported contrasts. It also does not say whether the listed p-values are adjusted for multiple testing. In the absence of that information, they are best read as the p-values attached to the reported sponsor analyses, not assumed to control the overall chance of a false-positive finding across all comparisons.

Multiplicity can arise when several doses, treatment comparisons, endpoints, or time points are examined. In general, the more questions tested, the more important it is to define which comparisons are confirmatory and how error rates are controlled. A prespecified hierarchy or adjustment can address some of these issues, but the registry record does not report such a plan. The range of secondary outcomes and the extension outcomes also means the primary endpoint is only one part of a broader outcome set; the record does not describe a testing hierarchy across those outcomes.

The stated full analysis set includes randomized participants who received at least one dose and had baseline data or at least one post-randomization observation for the endpoint. The registry does not report the number excluded under each criterion, the amount or pattern of missing endpoint data, or the reasons for missingness. It also does not report the method used to handle missing measurements in the longitudinal analysis, or sensitivity analyses testing alternative assumptions about missing data. These omissions limit assessment of how robust the estimated contrasts are to missing outcomes.

Diary measurement creates an additional reporting question because the endpoint was calculated from diary days, and the required recording period is described as 4 to 10 days. The record does not report completeness by group or how partial diary records were used. The treatment assignment, endpoint analysis population, and safety population should not be presumed to have identical membership. These are distinct descriptions in the registry, and the reported denominators vary by outcome and group.

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: osteoarthritis (0.9%), cerebrovascluar accident (0.9%), pneumonia (0.8%), gatrooesophageal reflux disease (0.8%), foot fracture (0.8%).

The registry reports serious adverse events and other adverse events by study group. In Part 1, serious adverse events were reported for 2 participants in the placebo group, 1 in the vibegron 3 mg group, none in the vibegron 15 mg group, 1 in the vibegron 50 mg group, none in the vibegron 100 mg group, 1 in the tolterodine ER 4 mg group, and 1 in the combination/sequential-treatment group. The corresponding serious-event denominators are reported separately by group. These are counts, not comparative estimates adjusted for follow-up or other factors.

For the extension, serious adverse events were reported for 14 participants receiving vibegron 50 mg, 8 receiving vibegron 100 mg, 18 receiving tolterodine ER 4 mg, and 1 receiving vibegron 50 mg with tolterodine ER 4 mg. The registry also lists serious-event terms, including osteoarthritis, cerebrovascular accident as spelled in the record, pneumonia, gastroesophageal reflux disease as spelled in the record, foot fracture, and dizziness, with percentages attached to those terms. These listed terms do not describe every event or establish a causal relationship to treatment.

Death counts are not reported in the registry record. Counts of participants with an event should be interpreted with the group-specific numbers at risk, treatment period, and event definitions in mind. The posted figures alone do not establish whether differences between groups are meaningful, and the safety summaries do not replace review of event timing, severity, and clinical context.

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

The results describe estimated changes in a diary-based measure of average daily micturitions at Week 8 in Part 1. The group estimates are negative, including the placebo estimate, and the sponsor reports model-based comparisons against placebo. The reported contrasts are more directly relevant to the comparative question than the within-group changes. Their confidence intervals communicate uncertainty about the estimated average differences, while the p-values describe the results of the sponsor’s specified analyses under their statistical assumptions.

These findings do not establish that every participant experienced a change like the group average. They do not show how many individuals had improvement, no change, or worsening, because those distributions are not reported for the primary endpoint in the information. The endpoint is one frequency measure based on diaries, not a complete measure of symptom burden or quality of life. The registry also lists incontinence and strong-urge outcomes, but those outcomes do not alter what the primary endpoint measures.

The Week 8 results do not by themselves establish what happened during the extension or whether effects persisted over the longer period. Extension assignments followed different earlier treatment histories, so extension-group comparisons cannot automatically be interpreted in the same way as comparisons within the randomized base study. The registry lists extension outcomes, but their results are not included in the primary estimates.

The findings also do not establish a dose-response relationship simply because several doses were studied and the reported point estimates differ. A formal dose-trend analysis is not reported in the registry record. Likewise, the p-values for individual comparisons should not be taken as definitive evidence across all doses and outcomes without knowing the multiplicity plan.

Finally, these registry results are not medical advice and do not determine which treatment is appropriate for an individual. They are statistical summaries of a clinical study, subject to the analysis population, diary measurements, model assumptions, missing-data reporting, and safety information available in the registry record. Broader conclusions require the full study context and careful evaluation of both benefits and harms.

14. Why This Trial Matters Statistically

This trial is statistically informative because it compares several vibegron doses with placebo and includes an active comparator, while reporting a continuous diary-based endpoint. The set of dose groups makes it possible to examine whether estimated changes vary across doses, but the presence of multiple doses is not itself a statistical test of a dose trend. The registry’s primary hypothesis explicitly refers to a dose-related reduction, while a trend analysis is not reported in the registry record. That gap highlights the distinction between a design question and the particular results posted.

The example also illustrates why within-group change and between-group effect are different quantities. The placebo group had a negative estimated change from baseline, as did the active-treatment groups. Comparing the change within one group to zero would not answer whether that group changed more than placebo. The sponsor’s model-based contrasts address the comparative question more directly, and their confidence intervals show the precision of those estimates.

Several reported comparisons have intervals that exclude zero and others do not. That pattern is useful for understanding the individual estimates, but it must be considered alongside the number of comparisons and the absence of a reported multiplicity strategy. Statistical interpretation depends not only on whether a particular p-value crosses a conventional threshold, but also on how the analysis was planned, how many hypotheses were considered, and whether the result is precise enough to be informative.

The study also shows why outcome definitions and analysis populations matter. The endpoint is calculated from diary days, and the full analysis set has specific treatment and data requirements. The record does not fully describe incomplete diaries, missing follow-up data, or sensitivity analyses. These features affect how readers judge the reliability and generalizability of model-based estimates.

Finally, the presence of safety counts alongside efficacy estimates encourages a balanced statistical reading. Event counts are descriptive and are not, on their own, causal comparisons. Keeping outcome, population, time point, and uncertainty aligned is essential when interpreting any clinical trial result.

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.

Several trial-specific limitations arise from the information reported in the registry record. The primary endpoint depends on participant voiding diaries, but the record does not report diary completion by group, the handling of incomplete diary periods, or how many observations contributed to each endpoint estimate. Variation in diary completeness could affect the precision and representativeness of the measured averages.

The analysis population definition excludes randomized participants who did not meet the stated treatment and data criteria. The registry does not report the reasons for exclusion or the amount and pattern of missing endpoint data. It also does not describe the missing-data assumptions or sensitivity analyses. This limits assessment of whether the sponsor’s estimates might change under alternative assumptions about outcomes that were not observed.

The registry identifies constrained longitudinal data analysis but does not report all model specifications needed to independently reproduce or fully evaluate the analysis. Details such as covariance structure, model terms, and diagnostic checks are not reported in the registry record. The randomization procedure, allocation concealment details, and masking procedures are also not reported in the information summarized for this analysis.

Multiple doses and several outcomes were studied. The record does not report whether the primary comparisons were adjusted for multiplicity, how confirmatory comparisons were prioritized, or whether the dose-related hypothesis was assessed with a formal trend test. The absence of this information makes it difficult to judge the overall false-positive risk across the set of analyses.

The primary estimate concerns Part 1 at Week 8, so it does not establish the result of the longer extension. Extension groups included participants with different earlier treatment histories, as described in the registry, and should not be treated as interchangeable randomized comparisons without further design details. Safety counts are also descriptive; the record does not report deaths, and the event summaries alone do not establish causation. Finally, the registry does not report the original sample-size justification, so the enrollment figure cannot explain the study’s design assumptions or its planned precision.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Efficacy and Safety of Vibegron (MK-4618) in Participants With Overactive Bladder (OAB) (MK-4618-008) — NCT01314872.
• Registry record last updated 2019-02-04; status last verified 2019-01.
• Results first posted 2016-06-17.
• 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 describes a completed Phase IIb randomized, double-masked, parallel-group study of vibegron, placebo, and tolterodine ER in participants with overactive bladder. Enrollment is reported as 1395. The primary endpoint was change from baseline in average daily micturitions at Week 8 in Base Study/Part 1, measured using voiding diaries. The full analysis set required randomization, at least one dose, and baseline data or at least one post-randomization observation for the endpoint.

Part 1 included placebo, four vibegron doses, tolterodine ER 4 mg, and a combination/sequential-treatment group. The sponsor reports constrained longitudinal data analysis comparisons against placebo for four vibegron doses and tolterodine ER. Estimates are negative for all Part 1 groups, including placebo; the contrast confidence intervals and p-values vary across comparisons. The record also reports serious adverse-event counts by group and lists secondary and extension outcomes.

The registry record does not report a multiplicity strategy, a dose-trend test, detailed missing-data handling, or the original sample-size justification. These absences constrain interpretation of the posted estimates, particularly across the multiple comparisons and outcomes.