Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040) (NCT01054300), a randomized phase 1 study. The primary outcome is Cumulative Urinary Glucose Excretion Over 0 to 24 Hours.

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, Phase 1 study with a cross-over design. The registry describes two dose cohorts and two treatment periods. In Cohort 1, the regimens were a single 2 mg morning dose and 1 mg in the morning plus 1 mg in the evening. In Cohort 2, the regimens were a single 4 mg morning dose and 2 mg in the morning plus 2 mg in the evening. Each regimen was given for one day, and the registry states that there was a washout period of at least 7 days between periods.

A cross-over design allows participants to receive more than one regimen in separate periods. In general, this can support comparisons within the same participants, since each participant may contribute observations under both regimens. However, the particular statistical model and the way the cross-over structure was incorporated into the primary analysis are not reported in the registry record. The posted outcome summaries list 25 participants for each Cohort 1 regimen and 24 participants for each Cohort 2 regimen; these are outcome-specific analysis counts, not necessarily counts of distinct participants across the whole cross-over study.

The registry reports 52 participants enrolled, with study start on 2010-02-17, primary completion on 2010-04-07, and status listed as completed. The primary outcome was urinary glucose excretion collected over the day after dosing. Although placebo is listed among the interventions and the brief description calls the study four-arm, the posted primary outcome summaries cover the once-daily and twice-daily active regimens. Further details of allocation procedures, sequence generation, concealment, and any design assumptions 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.

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: Analysis population included randomized participants who received assigned dose and had urine collection during all of the collection time frames between 0 and 24 hours following the morning dose.

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: All randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Cumulative Urinary Glucose Excretion Over 0 to 24 Hours, measured over 0 to 24 hours after the morning dose.

The primary endpoint was cumulative urinary glucose excretion from 0 to 24 hours after the morning dose, measured in grams. Urine was collected at prespecified intervals: 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours. Participants emptied their bladder just before dosing, and collection began after the morning dose. Summing collection across these intervals represents the total urinary glucose excreted during the defined observation period.

This endpoint was used to assess a pharmacodynamic response to the dosing schedules. In general, a pharmacodynamic measure describes a biological response associated with a treatment, while pharmacokinetics describes how drug exposure changes over time. The trial's stated objective included both pharmacodynamic and pharmacokinetic evaluation, but the posted primary outcome is the urinary glucose measure.

The outcome is a short-term measure following a single day of dosing, not a measure of long-term glycemic control or a clinical health outcome. Its interpretation depends on complete urine collection across the specified intervals. The registry's analysis population definition required urine collection during all intervals, so participants without a complete collection were not included in that population. The registry does not report further details about collection-quality checks, missing-interval handling, or the precise statistical model used to calculate the least-squares means.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is reported as a least-squares mean with a 90% confidence interval for each regimen. Least-squares means are generally model-based estimates of group means. In general, a model can account for specified features of a study design or adjust for covariates, but the registry does not state which model terms or covariates were used for these estimates. The label alone does not identify the adjustment strategy, so the values should be described as the posted least-squares means rather than as estimates adjusted for any particular factor.

What the confidence intervals communicate

In general, a confidence interval describes statistical uncertainty around an estimate under the method's assumptions. A narrower interval indicates greater precision than a wider interval on the same scale, while an interval does not show the full range of individual participant outcomes. The reported intervals are 90% confidence intervals for each regimen mean. They are not confidence intervals for the difference between regimens, and they do not directly answer whether the schedules differ. A contrast-specific estimate and interval would be needed for that question.

The reported outcome values are expressed in grams and refer to cumulative urinary glucose excretion over 0 to 24 hours after the morning dose. They are summaries for participants meeting the primary analysis-population definition, which required assigned treatment and urine collection in all specified time frames. The registry does not provide individual participant measurements or a distributional summary sufficient to describe variation among participants. It also does not report the calculation details for the least-squares means or confidence intervals.

Why the cross-over structure matters

In general, a cross-over study assigns participants to receive study regimens in separate periods, often allowing comparisons that account for stable differences between participants. Such designs also require attention to period, sequence, and possible carryover effects. The registry describes two periods and a washout of at least 7 days, but it does not report whether period or sequence terms were included in the analysis, how carryover was assessed, or what assumptions supported the analysis. Those details should not be inferred from the design label.

The outcome counts are reported separately for each regimen: 25 in each Cohort 1 summary and 24 in each Cohort 2 summary. Because this is a cross-over design, those counts should not be added as if they necessarily represented different people. Nor do the counts by themselves establish how many participants contributed complete pairs of observations. The registry's analysis-population description indicates that participants needed complete urine collection across the intervals, but it does not state how many otherwise eligible participants were excluded or why.

What is and is not a treatment comparison

The two regimens within each cohort use the same total daily dose, split differently across morning and evening. The reported arm-level means allow the reader to inspect each regimen's estimated urinary glucose excretion. They do not substitute for a treatment contrast. A contrast would quantify the estimated difference between schedules, with an uncertainty interval and, if reported, a test result. No such formal comparison is reported for the primary outcome.

In general, a non-significant test would not establish that two regimens are equivalent, and overlapping confidence intervals for separate means are not a substitute for a test of the difference. Conversely, these summaries do not justify a claim of a statistically significant difference. The registry record does not report a prespecified equivalence or noninferiority margin or a corresponding analysis. It also does not report an adjusted or unadjusted p-value for the primary comparison.

Precision and study planning

Precision refers to the uncertainty around an estimate, as represented in part by its confidence interval. The interval width depends on the data and on the analysis method. In general, increasing the amount of information can improve precision, but no observed effect or confidence interval should be converted into a claim about the probability that a result is true. Planning sample sizes calculated from an observed effect are planning illustrations, not observed power; the registry does not report a sample-size justification or the calculations underlying the trial's enrollment target.

The registry does not report whether interim analyses were planned or conducted, nor does it report the detailed statistical analysis plan. Consequently, details such as the model specification, handling of potential period effects, treatment of deviations, and inferential procedure for the schedule contrast are not reported in the registry record. The available information supports a careful descriptive reading of the regimen means and their intervals, but not a reconstruction of the full analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, but no secondary outcome results are posted. The primary outcome summaries are available for the four active dosing regimens, while a formal contrast between schedules is not reported. The registry record does not describe a multiplicity strategy, such as a hierarchy of hypotheses or adjustment for multiple comparisons. It is therefore not possible to determine from the record how multiplicity was considered in any inferential analyses.

The primary analysis population included randomized participants who received the assigned dose and had urine collection during all collection time frames from 0 to 24 hours after the morning dose. This definition makes complete collection a condition for inclusion in the primary population. The registry does not report the number of randomized participants who failed to meet this condition, reasons for incomplete collections, or methods for handling missing observations. It also does not report whether any alternative analysis population was used.

In general, excluding participants with incomplete outcome collection can affect interpretation if completeness is related to treatment or to the outcome. That is a general consideration, not evidence that such bias occurred in this study. The record does not provide enough information to assess the pattern or consequences of missing data. Details about intention-to-treat analyses, imputation, sensitivity analyses, and protocol deviations are not reported in the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events in each of the four active-regimen groups and zero deaths in each group. The groups had 25 or 26 participants at risk for serious adverse events, depending on the regimen. These counts describe the posted safety record for the groups and observation period; they do not establish that serious events could not occur or that the regimens have equivalent safety.

Other adverse events were reported for 5 participants in the Cohort 1 twice-daily group, 8 in the Cohort 1 once-daily group, 3 in the Cohort 2 twice-daily group, and 5 in the Cohort 2 once-daily group. The registry does not provide serious adverse event terms because none are listed. It also does not provide details in these summaries about event type, severity, timing, relationship to treatment, or whether one participant experienced more than one event.

In general, safety counts are best interpreted with their group sizes, follow-up period, and event definitions in mind. This was a single-day dosing study, and the posted counts cannot describe long-term risks. The registry's at-risk counts vary from the primary outcome counts, so safety and efficacy denominators should not be treated as interchangeable.

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

The primary results describe estimated urinary glucose excretion during the 24 hours after a morning dose for two dosing schedules in each of two dose cohorts. The least-squares means and their 90% confidence intervals provide a short-term, regimen-specific summary. The study's cross-over design means participants received regimens in separate periods, and the posted outcome population requires complete urine collection across all defined intervals.

These results do not, by themselves, answer whether once-daily and twice-daily dosing differ. The record does not report a formal estimate of the schedule contrast, its confidence interval, or a p-value. Separate regimen means are not the same as a direct comparison. In general, a comparison needs to account for the study design and quantify uncertainty around the difference. The details of such an analysis are not reported in the registry record.

The endpoint is a pharmacodynamic measure following one day of dosing. It is not a direct measure of long-term glycemic control, complications, quality of life, or other clinical outcomes. The registry's stated objective also includes pharmacokinetic evaluation, but the posted primary outcome summaries concern urinary glucose excretion. Results for other outcome measures are not posted.

The registry reports no serious adverse events or deaths in the listed active-regimen groups, alongside counts of other adverse events. Those short-term counts do not establish the safety profile over longer exposure or in populations beyond the enrolled adults with type 2 diabetes. The sample-size justification, detailed analysis plan, and missing-data methods are not reported. Accordingly, the results should be understood as short-term summaries from a small Phase 1 study, not as a complete assessment of comparative clinical benefit or risk.

13. Why This Trial Matters Statistically

This study illustrates how a cross-over trial can frame a dosing-schedule question while holding the total daily dose constant within each cohort. The Cohort 1 comparison concerns a total daily dose of 2 mg, and Cohort 2 concerns a total daily dose of 4 mg. The practical statistical question is not merely whether each regimen has a measurable outcome mean, but how the within-cohort schedule contrast was estimated and how uncertainty around that contrast was quantified.

The registry posts least-squares means and 90% confidence intervals for the individual regimens, but no formal comparison estimate. That distinction is important: descriptive summaries can show the level and precision of each regimen's outcome estimate, but they do not directly establish a difference between schedules. In general, the contrast should be interpreted using an estimate and uncertainty measure appropriate to the cross-over design.

The trial also makes the analysis population consequential. Complete urine collection across every specified interval was required. This is a reasonable feature to make explicit for a cumulative collection endpoint, but the record does not state how many participants had incomplete collections or how missing data were otherwise addressed. Reporting those details would help readers understand which observations informed the outcome summaries.

Finally, this Phase 1 evaluation has a narrow time horizon and a pharmacodynamic primary endpoint. Its statistical contribution is therefore about measurement, design, and the precision of short-term summaries, rather than long-term clinical outcomes. The absence of detailed model and multiplicity information limits independent assessment of inferential claims, while the posted arm-level estimates remain useful for understanding the scope and form of the available evidence.

14. 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 primary endpoint reflects urinary glucose collected over 0 to 24 hours following a single day of dosing. It provides a short-term pharmacodynamic outcome and cannot characterize longer-term treatment effects. Although the study objective included pharmacokinetic assessment, the primary result summaries discussed in the registry concern urinary glucose excretion.

The registry reports arm-level least-squares means and 90% confidence intervals but does not report a formal comparison between the once-daily and twice-daily schedules. It also does not report a p-value or confidence interval for that contrast. The detailed analysis model, including any handling of period or sequence effects in the cross-over design, is not reported in the registry record. This limits assessment of how well the posted summaries reflect the design.

The primary analysis population required receipt of assigned dose and complete urine collection across all specified intervals. The registry does not report the number of participants excluded under this definition, the reasons for incomplete collections, or any missing-data sensitivity analyses. The outcome counts for each regimen do not by themselves show how many participants contributed paired measurements.

Further limitations are that no secondary outcome results are posted, multiplicity methods are not reported, and the sample-size justification is not reported in the registry record. The brief study description includes the phrase sponsor open while the registry identifies the study as double-blind; the record does not explain that wording. The posted safety summaries do not provide event terms or longer-term follow-up. These gaps constrain interpretation beyond the short-term descriptive findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040) — NCT01054300.
• Registry record last updated 2019-11-21; status last verified 2019-11.
• Results first posted 2018-11-07.
• 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.

18. Record Summary

The registry identifies NCT01054300 as a completed, randomized, double-blind Phase 1 cross-over study sponsored by Merck Sharp & Dohme LLC. It enrolled 52 adults with type 2 diabetes. The study compared single-day once-daily and twice-daily ertugliflozin regimens in two dose cohorts, with a washout of at least 7 days between periods.

The primary outcome was cumulative urinary glucose excretion over 0 to 24 hours after the morning dose. The registry posts least-squares means and 90% confidence intervals for the four active regimens, with outcome counts of 25 for each Cohort 1 regimen and 24 for each Cohort 2 regimen. A formal schedule contrast is not reported. The record lists 11 outcome measures but no secondary results, and it does not report detailed statistical methods, multiplicity handling, or missing-data procedures.