The Role of P-glycoprotein in Sitagliptin Clinical Pharmacology: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Role of P-glycoprotein in Sitagliptin Clinical Pharmacology (NCT01112670), a randomized phase 4 study. The primary outcome is Sitagliptin Monotherapy: Sitagliptin Area Under the Plasma Concentration-time Curve (AUC) From 0 to Infinity.

2. Clinical Question

The trial's stated purpose was to examine pharmacogenetics, pharmacokinetics, and drug-drug interactions involving sitagliptin. The primary endpoint focuses specifically on sitagliptin exposure during monotherapy, rather than directly measuring a clinical health outcome. AUC from infinity represents the concentration-time exposure over the measured period and its extrapolation beyond the final observation.

The genotype groups supply the comparison of interest: participants are classified by ABCB1 genetic make-up, and the primary analysis compares their mean AUC values. The outcome description identifies the analyzed population as participants who completed both periods of the crossover study. The registry record does not report how participants were assigned to or sequenced through the periods, or how genotype status was determined.

This is a pharmacokinetic question in healthy participants. It is not a direct test of symptom improvement, disease control, or a clinical benefit. The reported group comparison can describe whether the observed AUC values differed across the listed genotype categories, but it cannot by itself establish a mechanism or explain the cause of any observed variation.

3. Trial Design

The registry record describes a phase 4, randomized, unmasked crossover study sponsored by the University of Colorado, Denver. The condition is listed as healthy, and the study status is completed. The recorded study start is 2009-11, and primary completion is 2011-07. Enrollment was 33.

The crossover design indicates that participants completed both periods, according to the primary outcome population description. The details of the periods, their sequence, any washout interval, and the treatment received in each period are not reported in the registry record. The primary outcome is explicitly labeled sitagliptin monotherapy, while the arm descriptions list a single 100 mg sitagliptin dose and five 40 mg atorvastatin doses in each genotype group. The registry record does not clarify the period-by-period relationship between those descriptions and the monotherapy endpoint.

Three groups are defined by ABCB1 genetic make-up: CGC/CGC, CGC/TTT, and TTT/TTT. The primary analysis reports an ANOVA across the three groups. The registry record identifies randomization but does not report its unit or method. Masking is listed as none.

The primary endpoint is continuous: sitagliptin AUC from infinity, measured in ng*hr/ml. The endpoint timeframe lists observations at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 hours post-dose. The registry record also lists secondary sitagliptin outcomes for AUC from infinity, maximum plasma concentration, and renal clearance in the sitagliptin-plus-atorvastatin setting. Specific analysis procedures beyond the reported ANOVA are not described 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 (n=145) were genetically pre-screened for ABCB1 1236/2677/3435 diplotypes. Those who possessed the needed ABCB1 genetic diplotypes, along with requisite clinical inclusion criteria, were started in the study (n=33).

Sitagliptin to Sitagliptin+Atorvastatin

Sitagliptin+Atorvastatin to Sitagliptin

Analysis population for the primary outcome, as defined in the registry: The population analyzed included participants who completed both periods of the pharmacokinetic crossover 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 Sitagliptin Monotherapy: Sitagliptin Area Under the Plasma Concentration-time Curve (AUC) From 0 to Infinity, measured over 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 hours post-dose.

The primary endpoint is sitagliptin area under the plasma concentration-time curve from 0 to infinity, abbreviated AUC. It summarizes drug concentration over time: larger AUC values represent greater measured overall plasma exposure during the defined observation and extrapolation period. The registry record gives the unit as ng*hr/ml and reports the outcome as a mean with standard deviation.

Concentration measurements were scheduled at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 hours post-dose. AUC from infinity is used in pharmacokinetic studies because it aims to capture exposure over the full concentration-time profile, including the portion beyond the last scheduled measurement. The registry record does not describe the method used to estimate that extrapolated portion.

For this study, AUC provides a continuous measure for comparing sitagliptin exposure among the ABCB1 genotype groups. It is a pharmacokinetic measure, not a direct measure of a clinical health outcome. The registry record labels the primary outcome as sitagliptin monotherapy. It separately lists secondary outcomes for sitagliptin AUC, maximum plasma concentration, and renal clearance with atorvastatin. These measures address drug exposure and handling; they do not alone establish clinical benefit or harm.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the reported ANOVA test?

Analysis of variance, or ANOVA, is a method for assessing whether the means of multiple groups are compatible with a common mean. In this study the reported ANOVA covers the three ABCB1 genotype groups and the continuous AUC endpoint. Its overall p-value addresses the group comparison as a whole; it does not indicate which specific groups might differ. Pairwise results are not reported in the registry record.

ANOVA evaluates observed variation between group means relative to variation within groups. The group standard deviations describe within-group dispersion, while the ANOVA combines information across groups according to its model. General statistical interpretation depends on assumptions about the observations and model errors. The registry record does not report diagnostic checks, transformations, covariate adjustments, or a fuller specification of the ANOVA.

How should means and standard deviations be read?

A mean is the arithmetic average of the values in a group. A standard deviation describes how spread out individual values are around that mean. It is not the uncertainty interval for the mean: estimating the mean's precision also depends on the number of analyzed observations and the statistical model. The registry record reports group means and standard deviations but does not provide confidence intervals for them.

The primary measure is continuous and reported in ng*hr/ml. The values represent AUC from infinity, a measure of exposure across the plasma concentration-time profile. AUC values do not directly express a clinical outcome. Their interpretation is tied to the pharmacokinetic question and the study's measurement and analysis procedures.

What does a p-value convey?

In general, a p-value describes how unusual data at least as incompatible with a specified null model would be if that model and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, nor a measure of the magnitude or clinical importance of a difference. The reported value, 0.83, is the registry's overall ANOVA result. The record does not provide a confidence interval or an effect estimate for the genotype-group comparison, so the precision of the contrast cannot be fully assessed from that p-value alone.

Why can a non-significant result remain uncertain?

Failure to identify a statistically detectable difference is not proof that all underlying group means are equal. A study can yield an imprecise estimate when the data are variable or the analyzed groups are limited in size. General statistical practice therefore considers effect estimates and their uncertainty, not only a p-value. In this record, group summaries and group analysis counts are available, but confidence intervals and pairwise estimates are not reported. This makes it difficult to determine which range of differences is compatible with the data.

What does the crossover description add?

A crossover study measures participants in more than one period, allowing within-participant comparisons when the relevant outcomes and treatment periods are specified. The primary population description confirms completion of both periods. In general, crossover analyses need to account appropriately for repeated measurements and for period or sequence effects where relevant. The registry record does not report the period sequence, the model's treatment of repeated observations, or assessments of carryover. It is therefore not possible to determine those details from the posted analysis description.

What can be recalculated from the posted summaries?

A simple unadjusted recalculation can be useful when a comparison has the needed summary statistics and its structure is appropriate. Here the posted primary analysis is an overall three-group ANOVA, while a two-arm recalculation for this continuous endpoint is not estimable from the record. No recalculated contrast or confidence interval is reported. The sponsor's reported ANOVA is therefore the available inferential result; the group means and standard deviations are descriptive summaries rather than a substitute for that analysis.

More generally, a confidence interval gives a range of estimates compatible with the data and the assumptions of a procedure. Its width reflects precision: a wider interval indicates more uncertainty. No confidence interval for the overall comparison or for pairwise differences is reported in the registry record. The record also does not report the statistical analysis plan, sample-size justification, interim analyses, or a multiplicity procedure. These absences limit evaluation of how the analysis was planned and how other outcomes were handled.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("ABCB1 Group 1", "ABCB1 Group 2", "ABCB1 Group 3")
n   <- c(9, 10, 10)
m   <- c(3638, 3502, 3129)
sp  <- c(1439, 1133, 795)
sd  <- sp      # posted standard deviations
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  ABCB1 Group 1  9  3638.000  1439.000  2531.887  4744.113
CARM  ABCB1 Group 2  10  3502.000  1133.000  2691.501  4312.499
CARM  ABCB1 Group 3  10  3129.000  795.000  2560.291  3697.709

11. Analyses Reported by the Sponsor

The registry record reports the sponsor's overall ANOVA across the three ABCB1 genotype groups, with p = 0.83. It also gives each group's mean and standard deviation. Those summaries are descriptive; the ANOVA is the reported inferential comparison. The record does not include a confidence interval for that comparison or pairwise estimates.

A two-arm recalculation is not available for this continuous endpoint from the posted information. The reported analysis compares three groups overall, and the registry record does not provide the information needed to present a corresponding two-arm recalculated result. There is therefore no recalculated estimate to set against the sponsor's result. The record marks no discrepancy between an available recalculation and the sponsor analysis; the sponsor's ANOVA remains the stated statistical result.

The p-value of 0.83 should be interpreted as the reported overall test, not as a measure of the size or precision of a difference. The group means and standard deviations help describe the observed data, but do not replace the inferential analysis or provide uncertainty intervals. The registry record does not report the model details needed to independently assess how repeated crossover measurements were handled.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary endpoint: sitagliptin monotherapy AUC from infinity. It also lists three secondary outcomes, concerning sitagliptin AUC, maximum plasma concentration, and renal clearance in the sitagliptin-plus-atorvastatin setting. The record reports 11 outcome measures and 11 analyses, but the numerical results available for interpretation include only the primary endpoint summaries and the overall ANOVA. Results for the secondary outcomes are not reported in the registry record.

When a study evaluates multiple outcomes or multiple comparisons, the chance of at least one apparently notable result can increase. Statistical approaches can account for multiplicity, but the registry record does not report whether any adjustment was planned or used. It also does not state a hierarchy for the outcomes or identify which analyses were prespecified. The primary outcome label alone does not resolve those questions.

The primary analysis population included participants who completed both periods of the crossover study. The registry record does not give the number of enrolled participants who completed both periods, the reasons for non-completion, or the number with missing endpoint values. It does not describe imputation, exclusion rules, or any sensitivity analysis for missing data. The recorded enrollment of 33 should not be assumed to be the number contributing to every outcome analysis.

The statistical analysis plan, sample-size justification, and any interim analyses are not reported in the registry record. Without those details, it is not possible to assess the planned handling of missing data, multiplicity, or analysis populations beyond the stated completer population. These limitations affect how fully the reported result can be evaluated; they do not change the values reported for the primary endpoint.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry record lists 33 participants at risk for serious adverse events and 0 affected. It lists 33 at risk for other adverse events and 24 affected. These are participant counts in the overall study population. The record does not report deaths; the deaths field is not populated. No serious adverse event terms are listed.

These counts describe what is recorded for this study population. They do not provide event severity or timing beyond the serious-versus-other classification, and the record does not give further descriptions of the other adverse events. The count of participants affected is not a measure of event frequency per person when the number of events per participant is unavailable. Percentages are not stated.

The safety counts should be interpreted separately from the pharmacokinetic endpoint and its ANOVA. The registry record does not report safety comparisons across genotype groups or treatment periods. The absence of recorded serious adverse events in this entry should not be extended to other populations or settings.

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

The result describes sitagliptin AUC from infinity in three ABCB1 genotype groups among participants who completed both periods of a pharmacokinetic crossover study. The reported group means are 3638.0, 3502.0, and 3129.0 ng*hr/ml, with standard deviations of 1439.0, 1133.0, and 795.0. The overall ANOVA p-value is 0.83. These are the registry's descriptive and inferential findings for the primary endpoint.

The result does not establish that the genotype groups have exactly the same AUC, because a non-significant overall test is not proof of equality. It also does not identify a particular pair of groups as different: pairwise estimates and tests are not reported. Without confidence intervals, the precision of the group comparisons cannot be fully judged. The outcome summaries describe observed variation but do not supply a complete account of uncertainty.

The endpoint is pharmacokinetic, not a clinical outcome. The study population is listed as healthy, and the primary analysis population consists of participants who completed both periods. The result therefore does not directly answer whether a medication improves a health condition or whether any finding applies to people with a disease. It also cannot by itself establish a biological mechanism involving P-glycoprotein.

The registry record describes both sitagliptin and atorvastatin interventions and lists secondary pharmacokinetic outcomes in the combination setting. The primary endpoint is specifically labeled sitagliptin monotherapy. Numerical results for the secondary outcomes are not reported in the available record, so the primary ANOVA cannot be used to infer those findings. Period-specific details and the analysis model are also not reported, limiting interpretation of the crossover structure.

In short, the record reports no statistically detectable overall difference in the primary AUC comparison, while leaving uncertainty about the size and precision of possible group differences. It is a focused result for this endpoint and analyzed population, not a general claim about pharmacokinetic equivalence or clinical effects.

15. Why This Trial Matters Statistically

This study presents a useful statistical distinction between a pharmacokinetic comparison and a clinical outcome comparison. AUC is a continuous measure of drug exposure, and the registry reports group means, standard deviations, and an overall test across genotype-defined groups. Those features allow readers to consider both the observed values and the inferential result rather than relying on a p-value alone.

The crossover design also makes analysis choices important. Measurements across periods can be related within participants, and a suitable analysis may need to reflect that structure. The registry record confirms completion of both periods for the stated primary analysis population, but does not describe how period or sequence effects were handled. This illustrates why a design label is not a full statistical methods description.

The reported ANOVA result provides an overall comparison, while the absence of pairwise estimates and confidence intervals limits more detailed interpretation. A non-significant result does not establish equivalence, and summary means alone do not show the uncertainty around contrasts. The record's clear separation of the primary monotherapy outcome from secondary combination outcomes is also important: evidence for one pharmacokinetic setting does not automatically describe another.

More broadly, the record demonstrates how a result can be statistically interpretable yet incomplete for some questions. The endpoint and group summaries are stated, but the analysis plan, missing-data handling, multiplicity approach, and detailed model are not reported in the registry record. Those distinctions help readers separate what the result directly supports from questions that remain 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 primary analysis is restricted to participants who completed both crossover periods, but the registry record does not state how many participants contributed to that analysis or explain non-completion. It also does not describe missing endpoint data or how missingness was handled. This limits assessment of potential selection related to the completer analysis.

The record gives an overall ANOVA result but does not report confidence intervals, pairwise comparisons, model details, or diagnostic checks. It does not explain how the crossover periods were modeled, whether sequence or period effects were considered, or whether carryover was assessed. The design description alone does not answer those questions.

There is also ambiguity in the record's descriptions: the primary outcome is labeled sitagliptin monotherapy, while each arm description lists both sitagliptin and atorvastatin doses. The record does not give period-by-period treatment details that would resolve this relationship. Accordingly, the primary endpoint should be interpreted according to its stated monotherapy label, without assuming additional protocol details.

The registry record does not report a sample-size justification, an analysis plan, interim analyses, or a multiplicity method. It lists secondary outcomes, but their results are not reported in the available record. Generalization is also limited by the stated healthy population and the pharmacokinetic nature of the endpoint. These limitations constrain interpretation but do not alter the reported means, standard deviations, or overall ANOVA result.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: The Role of P-glycoprotein in Sitagliptin Clinical Pharmacology — NCT01112670.
• Registry record last updated 2013-01-24; status last verified 2012-10.
• Results first posted 2013-01-08.
• 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

This completed phase 4 randomized, unmasked crossover study enrolled 33 healthy participants and was sponsored by the University of Colorado, Denver. The primary endpoint was sitagliptin monotherapy AUC from infinity, measured in ng*hr/ml, in participants who completed both periods. The analysis compared three ABCB1 genotype groups.

Group means were 3638.0, 3502.0, and 3129.0, with standard deviations of 1439.0, 1133.0, and 795.0, respectively. The reported overall ANOVA p-value was 0.83. Confidence intervals and pairwise results are not reported in the registry record. The record also lists secondary pharmacokinetic outcomes involving sitagliptin with atorvastatin, but their numerical results are not reported.

The result is a pharmacokinetic comparison in the stated analysis population, not a clinical outcome assessment. Details of the crossover analysis, missing-data methods, and multiplicity handling are not reported in the registry record.