Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386) (NCT03311841), a non-randomized phase 1 study. The primary outcome is Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1.

2. Clinical Question

3. Trial Design

This was a Phase 1, open-label, nonrandomized, parallel-group study with a fixed sequence and two periods. The registry record gives enrollment as 32 and describes the study as completed. The recorded start date is 2018-03-01, and the primary completion date is 2018-08-02. The sponsor is Merck Sharp & Dohme LLC.

The study population included healthy controls and participants with mild, moderate, or severe renal impairment, as well as participants with end-stage renal disease requiring hemodialysis. Severe impairment was described as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 without hemodialysis; moderate impairment as 30 to <60 mL/min/1.73m^2 without hemodialysis; and mild impairment as 60 to <90 mL/min/1.73m^2 without hemodialysis. Healthy controls were described as having creatinine clearance ≥90 mL/min. Participants with end-stage renal disease required hemodialysis.

The study description states that participants received a single oral dose of a microdose cocktail in Period 1. Its stated purpose was to characterize pharmacokinetic profiles in the presence and absence of rifampin. The registry record identifies groups receiving the cocktail alone and groups receiving the cocktail with rifampin for several renal-function categories. The available arm descriptions are truncated, so the complete period-by-period dosing details are not reported in the registry record information.

Nonrandom allocation and the fixed sequence matter when interpreting comparisons. These features mean that the groups are not randomized treatment arms, and differences between groups cannot automatically be attributed to rifampin or renal status alone. The registry record does not report further details on the allocation process or a protocol-based sample-size justification.

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

14-day Wash-out

Reasons for not completing this period:

Period 2

Analysis population for the primary outcome, as defined in the registry: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-inf for the following reasons: non-compliance with the protocol or high pre-dose concentrations.

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 Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1, measured over 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose.

The primary endpoint was AUC0-inf, the area under the plasma concentration-time curve from time zero, before dosing, to extrapolated infinite time. It was measured after the Period 1 dose and reported in pg*hr/mL. The registry description identifies the endpoint summary as a geometric least-squares mean with a 95% confidence interval.

AUC is used in pharmacokinetic studies because it represents overall systemic exposure across the measured concentration-time profile. Extending the area to infinite time requires extrapolation beyond the observed sampling interval. The registry lists post-dose sampling at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours, in addition to the pre-dose measurement. The endpoint therefore depends on both observed concentrations and the extrapolation described in the endpoint definition.

Geometric summaries are commonly used for pharmacokinetic measures because such measurements can be skewed; on a logarithmic scale, multiplicative differences are often easier to characterize. A confidence interval expresses uncertainty around the estimated endpoint, rather than the range of individual participant measurements. These are general statistical explanations, not additional findings from the study.

The registry record says the analysis population included participants compliant with study procedures who had available data. It also says participants could be excluded from the AUC0-inf analysis for protocol non-compliance or high pre-dose concentrations. Numerical geometric means and confidence intervals are not reported in the registry record information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as AUC0-inf, summarized by geometric least-squares mean and 95% confidence interval. The analysis population was described as participants compliant with study procedures who had available data. Participants were excluded from the AUC0-inf analysis for protocol non-compliance or high pre-dose concentrations. The registry record does not report further details of the model used to obtain the geometric least-squares means or confidence intervals.

What does AUC0-inf represent?

In general, area under the concentration-time curve combines concentration measurements across time into an overall exposure measure. AUC0-inf extends the measured area from the initial time point to an estimated infinite time. This extension necessarily involves extrapolation beyond the last observed measurement. The registry identifies sampling through 72 hours after dosing, with pre-dose and multiple post-dose measurements. The degree to which the extrapolated portion contributed to individual estimates is not reported in the registry record information.

Why use a geometric summary?

As a general statistical concept, pharmacokinetic measurements may be asymmetric, and a logarithmic scale can make multiplicative comparisons more natural. A geometric mean is based on averaging on the log scale and transforming back to the original scale. A geometric least-squares mean is typically a model-based summary, but the specific model and any covariates used in this study are not reported in the registry record information. The numerical estimates themselves are also not reported in the information.

How should a confidence interval be read?

In general, a confidence interval gives a range of values compatible with the data and the analysis procedure, reflecting uncertainty in an estimated quantity. It does not describe the range containing a specified proportion of individual participants, and it is not a guarantee that the true value lies within the particular interval. The registry states that the primary endpoint used 95% confidence intervals, but numerical interval limits are not reported in the information. Consequently, readers cannot judge the endpoint's precision from the endpoint definition alone.

What does the study design imply?

The registry identifies the allocation as nonrandomized, the masking as none, and the model as parallel, while describing a two-period fixed-sequence study. In general, nonrandomized groups may differ in characteristics other than the factor being examined. A fixed sequence also means that conditions are not assigned in a randomized order. These design considerations can complicate interpretation of contrasts across periods or groups. The record does not report enough detail to determine how such issues were handled analytically.

The study description names several renal-function groups, and the outcome listing includes pharmacokinetic measures for the cocktail components and rifampin-related assessments. A comparison of two estimated values is not automatically a causal effect. Interpretation depends on the estimand, model, group definitions, data completeness, and assumptions. Detailed model specifications, covariate adjustments, and the planned contrast definitions are not reported in the registry record information.

What do the planning illustrations mean?

General sample-size calculations use assumptions about the effect to detect, variability, significance level, allocation, and statistical method. The record describes illustrations based on a fraction of an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. For outcomes other than time-to-event outcomes, the stated convention is participants per arm for 80% power or 90% power. Time-to-event calculations use total events. These are planning illustrations, not observed power and not evidence that the study was originally designed around those assumptions. The registry record does not report its own sample-size justification.

For pharmacokinetic outcomes, variability and the scale of analysis can be especially important to planning. General calculations that use an observed effect can be sensitive to how that effect was estimated, and a planning illustration does not establish that a study had adequate precision for every endpoint or subgroup. Numerical illustration results are not reported in the information, so no specific planning estimate can be characterized.

What does over-dispersion mean in general?

For count outcomes, over-dispersion means that variation exceeds what a simple count model assumes. If present, it can make conventional uncertainty estimates too small unless the analysis accounts for it. This is a general methodological point; the registry record information does not report a count-model analysis or an assessment of over-dispersion for the adverse-event outcomes.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures and 127 analyses. It identifies one primary endpoint, AUC0-inf after the Period 1 dose, and lists secondary pharmacokinetic outcomes related to rifampin, including AUC0-24, AUC0-last, Cmax, C24, Tmax, t1/2, CL/F, and Vz/F. Because multiple outcomes, measures, and renal-function groups are involved, multiplicity is relevant: repeated testing can increase the chance of at least one apparently notable result when many hypotheses are assessed.

The registry record information does not report a multiplicity adjustment, a hierarchy for testing endpoints, or which analyses were confirmatory. It also does not report an interim-analysis plan or a complete statistical analysis plan. Without these details and the endpoint estimates, the strength of any individual statistical finding cannot be evaluated.

The primary endpoint analysis population was described as participants compliant with study procedures who had available data. The record specifies exclusion from the AUC0-inf analysis for protocol non-compliance or high pre-dose concentrations. It does not report the number excluded, the amount or pattern of missing endpoint data, or methods for handling missing values. Those details are important because exclusions and missingness can affect the analyzed population and the interpretation of estimates.

The registry record does not report whether all enrolled participants contributed to each outcome analysis, nor does the information give analysis-specific denominators. The stated analysis population should therefore not be assumed to be identical to the enrolled population for every outcome. No assumptions about the reasons for missing data or the impact of exclusions can be made from the available description.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure congestive (14.3%), acute kidney injury (14.3%).

The registry reports serious adverse events by study group, showing participants at risk and participants affected. Serious adverse events were recorded in the severe impairment, cocktail-alone group: 1 of 7 participants. The other listed groups each had 0 serious adverse events: end-stage renal disease with cocktail alone, 0 of 6; severe impairment with cocktail plus rifampin, 0 of 6; moderate impairment with cocktail alone, 0 of 6; moderate impairment with cocktail plus rifampin, 0 of 6; mild impairment with cocktail alone, 0 of 7; mild impairment with cocktail plus rifampin, 0 of 6; healthy control with cocktail alone, 0 of 6; and healthy control with cocktail plus rifampin, 0 of 6. No deaths were recorded in any listed group.

These are descriptive counts within small groups, not randomized comparative estimates. A count of zero does not establish that an event cannot occur, and the counts do not by themselves establish a difference between conditions. The registry also lists “Cardiac failure congestive” and “Acute kidney injury” among the top serious-event terms, each with 14.3%. The denominator and detailed relationship of these terms to the group-level counts are not reported in the registry record information.

Other adverse events were recorded in several groups, with none listed for either healthy-control group. The counts should be read as registry-reported observations and not as evidence of a causal relationship.

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

This study was designed to characterize pharmacokinetic profiles for a microdose cocktail across renal-function categories and in the presence and absence of rifampin. The primary endpoint, AUC0-inf, represents overall plasma exposure from the pre-dose time to extrapolated infinite time. The registry also identifies several secondary pharmacokinetic measures, including peak concentration, concentration at 24 hours, time to peak, half-life, apparent clearance, and apparent volume of distribution.

The registry information does not include numerical pharmacokinetic endpoint results. It therefore cannot establish the magnitude or direction of differences between renal-function groups, or between cocktail-alone and cocktail-plus-rifampin conditions. It also cannot show how precisely those differences were estimated. The study objective is not itself a result.

Even if numerical contrasts are considered elsewhere in the registry, the nonrandomized, open-label, fixed-sequence design requires careful interpretation. General statistical reasoning indicates that nonrandom allocation can leave group differences entangled with other participant characteristics, while fixed sequencing can make period and condition effects difficult to separate. The record information does not report enough analysis detail to assess how these issues were addressed.

The adverse-event counts describe observations in the listed groups. They do not establish that a drug caused an event or that one condition had a different risk from another. The small numbers in each group also mean that the counts alone provide limited information about uncommon outcomes.

Overall, the record describes a pharmacokinetic study question and its endpoint framework, but the numerical endpoint results, full analysis plan, and important details about missing data and model specification are not reported in the registry record information. The appropriate interpretation is therefore limited to the design, planned measures, and reported safety counts—not a conclusion about pharmacokinetic effects or treatment benefit.

13. Why This Trial Matters Statistically

The statistical interest of this study lies in its use of pharmacokinetic measures across distinct renal-function categories and its assessment of measurements with and without rifampin. AUC0-inf is a continuous exposure measure built from repeated plasma concentrations and an extrapolated tail. Other listed outcomes capture different aspects of the concentration-time profile, such as peak level, time to peak, and apparent clearance. These measures answer related but non-identical questions.

The design also highlights why the comparison structure matters. The registry describes a nonrandomized, open-label, fixed-sequence study, rather than a randomized treatment comparison. In general, an observed difference across groups can reflect the study condition as well as group composition, sequence, or other factors. Statistical summaries cannot by themselves remove design limitations, and interpretation depends on the analysis specification and its assumptions.

Multiplicity is relevant because the registry lists many outcomes and analyses across multiple groups and pharmacokinetic measures. A coherent analysis plan helps distinguish primary questions from exploratory ones and explains how uncertainty is handled across repeated comparisons. Those details are not reported in the registry record information, so the statistical status of individual analyses cannot be assessed.

The study also illustrates the distinction between a planning calculation and observed evidence. Sample-size illustrations based on observed effects are planning aids, not observed power and not proof that a study was designed to achieve a particular precision. The registry record does not report its own sample-size justification. These considerations make transparent reporting of estimates, confidence intervals, analysis populations, and exclusions especially important for evaluating pharmacokinetic 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 registry record describes a nonrandomized, open-label study with a fixed sequence. These features limit direct causal interpretation of contrasts. The record does not report how allocation occurred, whether period effects were assessed, or what adjustments were used in the statistical analyses.

The listed enrollment is 32, while the adverse-event groups have small participant counts. Small groups limit the information available from descriptive safety counts, particularly for uncommon events. The registry information does not provide numerical primary endpoint estimates or confidence intervals, preventing assessment of the magnitude and precision of the pharmacokinetic findings.

The primary endpoint analysis excluded participants for protocol non-compliance or high pre-dose concentrations, but the number of excluded participants is not reported in the registry record information. The amount and pattern of missing data, analysis-specific denominators, and any missing-data methods are also not reported. The record does not provide the complete statistical model, covariate choices, or multiplicity strategy.

The arm descriptions available in the registry record are incomplete, so full period-by-period dosing details are not reported in the registry record information. The record also does not report the study's own sample-size justification or an interim-analysis plan. These limitations leave important aspects of implementation, analysis, and precision unresolved.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386) — NCT03311841.
• Registry record last updated 2020-01-09; status last verified 2019-12.
• Results first posted 2020-01-09.
• 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

This completed Phase 1 study, NCT03311841, examined pharmacokinetics of a microdose cocktail containing midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin across renal-function groups, with and without rifampin. It was open-label, nonrandomized, parallel-group, and fixed-sequence, with enrollment of 32. The recorded start date was 2018-03-01, and primary completion was 2018-08-02.

The primary endpoint was AUC0-inf after the Period 1 dose, summarized as a geometric least-squares mean with a 95% confidence interval. The registry information does not report numerical primary endpoint results. Safety listings show no deaths and report serious adverse events in one listed group; the counts are descriptive and not randomized comparisons. Details on the full statistical plan, multiplicity handling, missing data, and the study's sample-size justification are not reported in the registry record information.