Study to Evaluate Effects of Probenecid, Rifampin and Verapamil on Bexagliflozin in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Effects of Probenecid, Rifampin and Verapamil on Bexagliflozin in Healthy Subjects (NCT03296800), a non-randomized phase 1 study. The primary outcome is Cmax (Maximum Observed Plasma Concentration).

2. Clinical Question

The study’s stated purpose was to examine drug–drug interactions involving bexagliflozin with three commonly prescribed medications and to evaluate safety and tolerability in those combinations. The endpoint description specifies blood sampling and non-compartmental analysis of plasma concentration data. A separate secondary outcome is urinary glucose excretion over 0–48 hours. The record does not provide numerical results for either the primary endpoint or that secondary outcome, so the size, direction, and precision of any pharmacokinetic or pharmacodynamic differences cannot be described from the registry record.

3. Trial Design

The registry describes a Phase 1, open-label, non-randomized, fixed-sequence composite study. Its allocation is recorded as non-randomized and its model as single-group. The study evaluated three medication sequences: bexagliflozin with probenecid, bexagliflozin with rifampin, and bexagliflozin with verapamil. The record reports enrollment of 48. Each sequence description identifies 16 healthy subjects, and each includes a bexagliflozin-alone period as well as a period involving the other medication.

The dosing schedules were sequential rather than randomized. For the probenecid sequence, the description says bexagliflozin was taken on Day 1, probenecid on Days 3 and 4, and both on Day 5; the description then ends before the Day 6 details are complete. For rifampin, bexagliflozin was taken on Day 1, rifampin on Days 3 to 5, and both on Day 6; the description ends before the Day 7 details are complete. For verapamil, the record says bexagliflozin was taken on Day 1 and verapamil one hour before bexagliflozin on Day 4. The incomplete schedule text does not support further detail about those sequences.

Open-label means the study was not masked, while non-randomized means treatment order or assignment was not allocated randomly. In general, a sequential within-study comparison can be useful for describing measurements under different exposure conditions, but it is not equivalent to a randomized parallel-group comparison. Time, order, and other changes between periods may affect interpretation; the registry record does not describe how such factors were handled analytically.

The record lists a start date of 2017-09-27, a primary completion date of 2017-12-06, and status as completed. The record does not report a control group randomized independently to a medication sequence, a washout description, or the rationale for the enrollment target.

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

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 Cmax (Maximum Observed Plasma Concentration), measured over Up to 48 hours.

The primary endpoint is Cmax, the maximum observed plasma concentration of bexagliflozin, expressed in ng/mL. It is a pharmacokinetic measure: it describes the highest measured concentration in the blood after administration during the specified observation period. The registry gives a timeframe of up to 48 hours.

The endpoint description says whole venous blood samples were collected before dosing and at specified post-dose times through 48 hours. Plasma concentration data were used to estimate pharmacokinetic parameters for each subject by non-compartmental analysis. Cmax is used in pharmacokinetic assessments because it characterizes peak observed exposure. Comparing Cmax across the study’s medication sequences could help describe whether peak bexagliflozin concentrations differed between the alone and co-administration periods. That interpretation requires the actual estimates and their uncertainty, which are not reported in the registry record.

In general, a maximum observed value depends on the sampling schedule: a peak occurring between collection times may not be captured exactly. The registry describes the collection schedule, but does not report the resulting Cmax estimates, their geometric coefficients of variation, or inferential results. The endpoint is listed as a geometric mean with geometric coefficient of variation as the dispersion measure. This choice describes concentration data on a multiplicative scale, but the registry record does not state the analysis details beyond the non-compartmental estimation described.

The listed secondary outcome is urinary glucose excretion over 0–48 hours. No result for that outcome is reported in the registry record. Cmax concerns plasma concentration and should not be treated as a direct measure of clinical benefit or as a complete summary of all pharmacokinetic or pharmacodynamic effects.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a pharmacokinetic study with Cmax as its primary endpoint. The explanatory points below are general statistical context; they do not assert that a particular unreported method was used.

What does Cmax measure?

Cmax is the largest observed plasma concentration during the defined sampling period. In general, pharmacokinetic studies use concentration measurements over time to describe drug exposure. The endpoint description states that blood was sampled before dosing and at multiple post-dose times through 48 hours. Non-compartmental analysis was used to estimate pharmacokinetic parameters from each subject’s concentration data. This method summarizes observed concentration-time information without requiring the reader to assume a specific compartment model. The registry does not provide the actual concentration-time data or the resulting Cmax estimates.

Why report a geometric mean?

The primary endpoint is specified as a geometric mean, with geometric coefficient of variation for dispersion. General statistical context: concentration measures are often right-skewed and are naturally interpreted multiplicatively. A geometric mean is calculated on a log scale and then expressed back on the original scale; it can summarize a typical level when relative rather than additive changes are of interest. A geometric coefficient of variation describes spread relative to the geometric mean. These summaries do not show the full distribution, and they do not by themselves indicate whether a difference between conditions is statistically distinguishable. Numerical geometric means, variability estimates, and uncertainty intervals are not reported in the registry record.

What does the sequence design imply?

The study is listed as non-randomized, open-label, and single-group, with fixed sequences. General statistical context: a within-subject sequence can compare measurements from the same subject under different conditions, which may reduce the influence of stable differences between subjects. However, measurements taken at different times can also be affected by period, order, or carryover effects. Randomization can help balance some sources of bias, but it is not part of the recorded allocation for this study. The registry record does not report how the analysis accounted for sequence or period, whether carryover was assessed, or the rationale for the sequence order. It also does not describe a washout period.

The comparator periods are bexagliflozin alone within each sequence. Because these are sequential conditions and not randomized parallel arms, comparisons should be understood in the design context rather than as independent randomized treatment-group contrasts. The registry’s own study description identifies the allocation as non-randomized, and the record does not report an adjusted comparison model.

How should uncertainty be understood?

General statistical context: a confidence interval gives a range of values compatible with the data and the method used, expressing uncertainty around an estimate. A narrow interval indicates greater precision than a wide interval, while an interval alone does not establish clinical importance. The registry record does not report confidence intervals for Cmax or the other listed outcomes, so precision cannot be evaluated from the posted results. No p-value for the primary endpoint is reported either.

Repeated measurements within subjects are not statistically independent in the same way as observations from separate participants. General analyses of repeated measures must account for that dependence when estimating uncertainty. The registry mentions subject-level non-compartmental parameter estimation, but does not describe the statistical method used to compare conditions or to obtain uncertainty estimates. It is therefore not possible to infer the comparison model from the endpoint description alone.

What do planning illustrations represent?

General statistical context: a sample-size illustration based on an observed effect asks how many participants might be needed under stated assumptions to detect an effect of a chosen size. Such a calculation is a planning aid, not a result of the trial and not observed power. The registry’s stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect set as a stated fraction of the observed effect. The record does not provide numerical illustration outputs or the fractions in this information. The assumptions are not evidence that the original study was designed using that calculation.

In general, power depends on the effect size, variability, analysis method, and design. A planning estimate based on an observed effect can be unstable, especially when the original estimate is imprecise. It should not be used to substitute for reported uncertainty around the trial’s estimates. The registry does not report a sample-size justification, target power, or the assumptions used in the original study design.

What is not available for evaluating the analysis?

The record lists five outcome measures and six analyses, but does not describe a complete statistical analysis plan, the model for between-condition comparisons, or any adjustment for multiple analyses. It also does not report the analysis population, missing-data handling, exclusions from analysis, or the number of participants contributing to each endpoint estimate. These omissions limit evaluation of how the results were generated and how robust they may be. Without numerical endpoint estimates, uncertainty measures, and analysis details, the primary pharmacokinetic question cannot be answered quantitatively from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and six analyses. It identifies Cmax as the primary endpoint and urinary glucose excretion over 0–48 hours as a secondary outcome. It does not report a full list of the analyses, explain whether multiple comparisons were planned, or state whether any multiplicity adjustment was used. The order or hierarchy among analyses beyond the primary and secondary outcome labels is not reported in the registry record.

General statistical context: when several outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase if each is assessed separately without accounting for the number of tests. A prespecified hierarchy or adjustment can help clarify how confirmatory conclusions should be drawn. The record does not indicate whether these approaches were used, so no claim about control of false-positive findings can be made.

The record does not report missing-data methods, the number of participants with evaluable Cmax data, exclusions, or the analysis population for the endpoint. The endpoint description says parameters were estimated for each subject using non-compartmental analysis, but does not explain how incomplete concentration profiles or unavailable measurements were handled. The registry record also does not report whether all enrolled participants completed every sequence or contributed data to each analysis.

These are reporting gaps, not evidence that data were missing or that an analysis was inappropriate. Without the analysis population and missing-data approach, readers cannot assess whether endpoint estimates reflect all enrolled participants or a subset with available measurements. Numerical estimates and their uncertainty are also absent, preventing independent assessment of the analyses’ results.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events, other adverse events, and deaths for six group-period entries: bexagliflozin alone and bexagliflozin with the additional medication in each of the three study sequences. Each entry lists 16 participants at risk. Serious adverse events are recorded as zero in every entry, and deaths are also recorded as zero in every entry.

For other adverse events, the record lists zero for Study 1 bexagliflozin alone, one for Study 1 bexagliflozin with probenecid, zero for Study 2 bexagliflozin alone, zero for Study 2 bexagliflozin with rifampin, two for Study 3 bexagliflozin alone, and zero for Study 3 bexagliflozin with verapamil. The registry does not provide terms or descriptions for these other events in the record summarized.

These counts are reported by group-period. Because the design is sequential, the entries should not be treated as independent randomized groups, and the counts should not be added to infer the number of distinct participants affected. Zero reported serious events in these entries describes the registry record; it does not establish that the risk of a rare event is absent. The record does not report additional detail about event severity, timing, relatedness, or collection methods.

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

This study addresses a focused pharmacokinetic question: how bexagliflozin concentrations, including maximum observed plasma concentration, were characterized when bexagliflozin was administered alone and in sequences involving probenecid, rifampin, or verapamil. It is a Phase 1 study in healthy subjects, according to the title and arm descriptions, and uses a non-randomized, open-label, fixed-sequence design. These features define the setting in which its results would need to be interpreted.

The registry record does not report numerical Cmax estimates or comparisons. It therefore cannot show whether peak concentration was higher or lower in any co-administration period, how large a difference may have been, or how precisely it was estimated. The listed endpoint and sampling method describe what was measured, not what the measurements found. The secondary outcome, urinary glucose excretion over 0–48 hours, is listed without numerical results as well.

The safety entries report zero serious adverse events and zero deaths in each listed group-period. Other adverse-event counts are also recorded, but the registry does not describe those events. These counts do not establish the presence or absence of risks beyond what was recorded, and they do not provide a complete basis for comparing safety between the sequential conditions.

General statistical context: a study’s design and sample size determine how much information its estimates can provide, while confidence intervals and other uncertainty measures show the precision of those estimates. The registry does not report those measures for the primary endpoint. Nor does it report the statistical comparison method, missing-data handling, or multiplicity approach. Consequently, the posted record is insufficient to judge statistical significance, clinical importance, or the robustness of a potential difference.

The study should not be interpreted as a randomized comparison or as evidence about treatment effects in people with Type 2 Diabetes Mellitus. Although that condition appears in the registry listing, the study title and arm descriptions specify healthy subjects. No clinical outcome results are reported. The record’s information supports describing the design, endpoint, and reported safety counts, but not a conclusion about whether any medication changes bexagliflozin exposure or about clinical benefit.

13. Why This Trial Matters Statistically

Drug-interaction studies ask whether the presence of another medication is associated with a change in a drug’s measured exposure. Cmax is one pharmacokinetic measure relevant to that question because it records the highest observed plasma concentration during the sampling period. The registry describes bexagliflozin sequences with probenecid, rifampin, and verapamil, alongside bexagliflozin-alone periods. That structure makes the study’s intended pharmacokinetic focus clear, even though numerical primary results are not reported.

Statistically, the design matters because the conditions were administered in a fixed sequence rather than assigned at random. Sequential measurements can contain within-subject information, but order and time may affect comparisons. Recognizing that structure prevents a mistaken reading of the entries as independent randomized arms. It also highlights the importance of reporting how analyses address repeated observations and possible period effects. Those analysis details are not reported in the registry record.

The study also illustrates the distinction between an endpoint definition and an endpoint result. A precise description of sampling times, units, and non-compartmental estimation explains how the primary measure was intended to be obtained. It cannot substitute for numerical estimates, variability, or uncertainty intervals. Without those results, readers cannot assess the size or precision of a possible difference between conditions.

Finally, the registry reports safety counts by group-period, while the sequential design calls for care in interpreting them. The serious adverse event and death entries are straightforward to describe, but the record offers little detail about other events. The study’s statistical contribution therefore depends on transparent reporting of both estimates and analysis methods, not merely on naming a pharmacokinetic endpoint. In this case, the available registry information makes the question and design legible while leaving the principal quantitative comparison unresolved.

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 principal limitation for interpreting the posted results is that numerical primary-endpoint findings are not reported in the registry record. Cmax is defined, and its unit, timeframe, and estimation approach are described, but estimates, variability values, confidence intervals, and p-values are absent. The secondary urinary glucose excretion outcome is listed without numerical results. This prevents assessment of direction, magnitude, and precision.

The study is non-randomized, open-label, and fixed-sequence. Its bexagliflozin-alone periods are not independent randomized controls. Sequence, period, and potential carryover effects may matter when interpreting measurements collected at different times; the registry does not report how these issues were assessed or handled. The dosing descriptions for the probenecid and rifampin sequences are incomplete in the record, which further limits reconstruction of the schedule.

The registry does not report a sample-size justification, a complete statistical analysis plan, the comparison model, multiplicity procedures, analysis populations, or missing-data methods. Although it lists five outcome measures and six analyses, it does not supply enough detail to evaluate the full analysis structure. It also does not report participant characteristics or endpoint-specific numbers contributing to the analyses.

The safety record gives counts for serious and other adverse events and deaths by group-period, but does not describe the other events or provide detail on timing, severity, or relatedness. Because the study uses sequential conditions, the entries cannot be treated as independent randomized groups or combined to infer distinct affected participants. These limitations constrain conclusions to the design and reported counts, rather than quantitative claims about pharmacokinetic differences or broader clinical outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate Effects of Probenecid, Rifampin and Verapamil on Bexagliflozin in Healthy Subjects — NCT03296800.
• Registry record last updated 2021-07-01; status last verified 2021-06.
• Results first posted 2021-04-27.
• 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 record describes NCT03296800, a completed Phase 1, open-label, non-randomized, fixed-sequence study of bexagliflozin with probenecid, rifampin, and verapamil in healthy subjects. Enrollment is reported as 48. The primary endpoint is maximum observed plasma concentration of bexagliflozin, measured in ng/mL over up to 48 hours and estimated using non-compartmental analysis. The listed secondary outcome is urinary glucose excretion over 0–48 hours.

The study includes bexagliflozin-alone periods within each medication sequence, but does not use randomized allocation. Numerical primary or secondary outcome results are not reported in the registry record. Serious adverse events and deaths are recorded as zero in each listed group-period; other adverse-event counts are reported without event descriptions. The record does not report the statistical comparison method, missing-data handling, or multiplicity procedures.