Drug Drug Interaction of BI 201335 and Tenofovir: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug Drug Interaction of BI 201335 and Tenofovir (NCT01340196), a non-randomized phase 1 study. The primary outcome is Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15.

2. Clinical Question

3. Trial Design

This completed phase 1 study, NCT01340196, is titled “Drug Drug Interaction of BI 201335 and Tenofovir.” Its stated objective was to evaluate the potential for an interaction when BI 201335 and tenofovir are administered together. The trial record describes a nonrandomized, unmasked, single-group design, with enrollment of 16. It does not describe a randomized control group or a blinded comparison.

The listed sequence began with tenofovir once daily for the first 15 days. BI 201335 was given twice daily from day 8 through day 22, with a morning dose only on day 22. This schedule makes Day 7 and Day 15 relevant time points for the primary tenofovir endpoint: Day 7 is before BI 201335 begins, and Day 15 is during the period when both drugs are scheduled. The primary endpoint title identifies tenofovir AUC on those days. Although the study objective also describes examining the effect of tenofovir on BI 201335 pharmacokinetics, the registry record does not provide a specific BI 201335 primary endpoint result.

The record lists Boehringer Ingelheim as sponsor and gives the study start as 2011-04 and primary completion as 2011-06. Its status is completed. The intervention is listed as tenofovir/BI 201335. The registry record does not report further details about allocation procedures beyond the nonrandomized designation, or details of any washout period or additional treatment sequences. The design should therefore be read as a scheduled within-sequence assessment, not as a like-for-like comparison of randomized groups.

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.

Treat. Period 1 (Tenofovir)

Treat. Period 2 (Tenofovir/Faldaprevir)

Treat. Period 3 (Faldaprevir)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants from the pharmacokinetic analysis set (PK set), including all subjects who were documented to have taken at least one dose of trial medication (treated set) who provided evaluable data for at least 1 observation for at least 1 primary PK endpoint without important protocol violations relevant to the evaluation of PK.

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 Steady-state Pharmacokinetics of AUC0-24 of Tenofovir on Day 7 and on Day 15, measured over 144:00, 144:30, 145:00, 145:30, 146:00, 147:00, 148:00, 150:00, 152:00, 156:00, 168:00 hours on day 7 and 168:00, 168:30, 169:00, 169:30, 170:00, 172:00, 174:00, 176:00, 178:00, 180:00, 192:00 hours on day 15.

The primary endpoint is steady-state tenofovir AUC from 0 to 24 hours, assessed on Day 7 and Day 15. AUC is the area under the plasma concentration–time curve over the specified interval. As a general pharmacokinetic concept, it represents overall drug exposure across that interval rather than a concentration at a single sampling time. The registry lists the unit as ng*h/mL and the summary measure as a geometric mean, with geometric coefficient of variation as the dispersion measure.

Comparing these scheduled measurements is relevant to the stated drug-interaction question because the treatment sequence places Day 7 before BI 201335 dosing begins and Day 15 during scheduled coadministration. A change in AUC between these assessments could describe a change in tenofovir exposure over the measured interval. The endpoint alone, however, cannot establish why a change occurred or whether it is attributable to the coadministered drug; interpretation depends on the design, data quality, and analysis.

The record describes plasma sampling times on Day 7 and Day 15 and defines the pharmacokinetic analysis population. It does not report the AUC estimates, their geometric coefficients of variation, a treatment contrast, or a confidence interval. Consequently, the size and precision of the observed comparison are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUC measure?

As a general pharmacokinetic concept, area under the concentration–time curve combines concentration information across a specified time interval. AUC from 0 to 24 hours concerns exposure over that interval, rather than a peak concentration or a single blood draw. Here, the registry defines the primary endpoint as steady-state tenofovir AUC0-24 on Day 7 and Day 15. The listed unit is ng*h/mL. The sampling schedule includes multiple plasma collection times for each assessment, but the registry record does not report the resulting AUC values.

Why use a geometric mean?

The endpoint summary measure is the geometric mean. As a general statistical explanation, pharmacokinetic measurements often vary proportionally: changes are naturally described as relative rather than additive. A geometric mean summarizes values on a logarithmic scale and then expresses the result on the original scale. This can be useful when measurements are positive and have a right-skewed distribution. It does not mean that every participant had a value close to the group summary, and it does not show the uncertainty of a comparison by itself.

The registry also identifies geometric coefficient of variation as the measure of dispersion. In general, a coefficient of variation describes spread relative to the scale of the values. A geometric coefficient of variation expresses variability in a way suited to log-scale pharmacokinetic data. It is not interchangeable with a confidence interval: the former describes dispersion among observations, while a confidence interval would describe uncertainty around an estimate or contrast. The record does not report the coefficient values or a confidence interval for the Day 7 and Day 15 comparison.

What does the scheduled comparison represent?

The sequence lists tenofovir once daily for the first 15 days and BI 201335 twice daily on days 8 through 22, except that only a morning dose is listed on day 22. The primary endpoint names Day 7 and Day 15. Thus, the endpoint compares a tenofovir assessment before BI 201335 dosing begins with a later assessment during scheduled coadministration. This is a within-sequence time comparison. It is not a randomized contrast between people assigned to separate treatment groups.

As a general design principle, a within-person comparison can reduce variation associated with stable differences between participants when the same people contribute measurements at both times. That benefit depends on paired observations and appropriate analysis. The registry record does not report how many participants had evaluable measurements at each time, whether all observations were paired, or the exact statistical model used. The analysis population definition allows inclusion when a participant has evaluable data for at least one observation for at least one primary pharmacokinetic endpoint; it does not establish complete data at both time points for every participant.

What can a confidence interval tell a reader?

As a general explanation, a confidence interval gives a range of values compatible with an estimate under the analysis assumptions. A narrow interval indicates greater precision than a wide interval, while the interval’s location helps show which directions and magnitudes remain plausible. It is not a guarantee that the true value lies within the interval, and it does not resolve biases arising from the design. No confidence interval for the primary comparison is reported in the registry record, so precision cannot be evaluated from the posted results.

How should significance testing be understood?

A p-value, when reported, measures 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, and it does not measure the size or clinical importance of an effect. The registry record does not report a p-value or the statistical test for the primary comparison. The sample-size assumptions mention a two-sided significance level of 0.05 for planning illustrations, but that assumption does not establish the test used for the trial analysis.

Why do design and variability matter?

For a single-group sequence, changes over time can reflect more than the coadministered treatment. General considerations include time-related changes, measurement variability, and missing observations. These are reasons to interpret a before-and-during comparison cautiously, not claims that any particular problem occurred in this study. The record does not describe an adjustment strategy or a statistical model that would address these considerations.

Pharmacokinetic data may also show over-dispersion, meaning variability is greater than a simple model would expect. As a general statistical point, a model that ignores substantial over-dispersion can give misleading standard errors and overly narrow uncertainty intervals. The geometric summary is consistent with describing pharmacokinetic values on a multiplicative scale, but the registry record does not report whether over-dispersion was assessed or how it was handled.

The planning assumptions describe an illustration based on the observed effect, with equal allocation between two arms and a normal approximation. They do not match the listed single-group design as a direct account of the trial’s analysis. Any such sample-size values are planning illustrations, not observed power. The registry record does not report the trial’s sample-size justification, interim analyses, or a detailed statistical analysis plan.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and 6 analyses. The primary endpoint is tenofovir AUC0-24 on Day 7 and Day 15, while the record also lists secondary safety outcomes. The registry record does not report whether statistical testing was adjusted for multiple outcomes, time points, or analyses, or whether a hierarchy of hypotheses was prespecified. Without that information, the family of tests and the intended control of false-positive findings are not reported in the registry record.

The primary pharmacokinetic analysis population is described as participants in the PK set who took at least one dose of trial medication and provided evaluable data for at least one observation for at least one primary PK endpoint without an important protocol violation. This definition helps identify the intended analysis population, but the registry record does not report the number included in the PK set or the number contributing to each Day 7 and Day 15 estimate. It also does not state how protocol violations were judged.

The record does not describe how missing pharmacokinetic measurements were handled, whether any values were excluded, or whether the primary comparison required paired observations. It does not report sensitivity analyses for missing data. As a general statistical matter, incomplete data can affect both the estimate and its precision, particularly when missingness is related to treatment or measured outcomes. There is not enough information in the registry record to determine whether missingness occurred or how it influenced the analysis.

The record also does not report the statistical model, standard-error method, confidence-interval method, or a detailed analysis plan. The planning assumptions do not fill these gaps: they are described as illustrations and do not establish the analysis actually used.

11. 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 lists serious adverse event figures for Tenofovir, Tenofovir/Faldaprevir, and Faldaprevir. For each category, 16 participants are listed as at risk and 0 as affected by serious adverse events. These are registry-reported category counts; the record does not explain how the categories relate to the treatment sequence or whether participants could appear in more than one category. They should not be added together to infer a total number of distinct participants.

The registry lists other adverse events separately: 1 affected participant for Tenofovir, 16 for Tenofovir/Faldaprevir, and 10 for Faldaprevir, with 16 at risk in each category. These figures are not the serious-event counts, and the record does not provide event-level details or establish that an event was caused by a particular treatment. The secondary outcomes also refer to drug-related adverse events and clinically relevant abnormalities for examinations, vital signs, safety laboratory tests, and ECGs, but detailed results for those outcomes are not included in the registry record reported for this analysis.

Deaths are not reported in the registry record. The serious-event counts are descriptive registry entries; they do not by themselves establish the absence of risk, particularly without event detail, follow-up context, or a comparison designed to estimate a treatment effect.

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

The trial’s stated purpose was to assess the potential for a drug interaction between BI 201335 and tenofovir. Its named primary endpoint focuses on tenofovir exposure, measured as steady-state AUC0-24 on Day 7 and Day 15. The dosing schedule places the Day 7 assessment before BI 201335 begins and the Day 15 assessment during scheduled coadministration. This makes the endpoint pertinent to the study objective, but the registry record does not report the AUC estimates or a numerical comparison.

Without those results, the posted data do not show whether tenofovir exposure changed, in which direction it changed, or how precisely any estimate was measured. The record also does not provide the specific result needed to quantify the reciprocal effect of tenofovir on BI 201335 pharmacokinetics, despite that broader objective in the official title. No conclusion about the size or clinical relevance of a pharmacokinetic interaction can be drawn from the endpoint description alone.

The design further limits what a comparison could establish. This is a nonrandomized, unmasked, single-group sequence, not a randomized comparison with a concurrent control group. A difference between the scheduled assessments would be a temporal within-sequence contrast; the design alone cannot distinguish a treatment-associated change from all other time-related influences. This does not mean that a change occurred, only that causal attribution would require careful interpretation.

The serious adverse event entries report zero affected participants in each listed category, with 16 at risk in each. Those figures are not a substitute for the missing pharmacokinetic results, nor do they demonstrate that no adverse effects occurred. Other adverse event counts are listed separately, and deaths are not reported in the registry record. Overall, the registry describes the question, schedule, endpoint, analysis-population definition, and some safety counts, but it does not report enough numerical primary outcome information to characterize the pharmacokinetic finding.

13. Why This Trial Matters Statistically

This study is statistically useful to examine because its endpoint and dosing sequence connect a pharmacokinetic question to a within-sequence comparison. Tenofovir AUC0-24 is assessed on Day 7 and Day 15, with BI 201335 scheduled to begin after the earlier assessment and to overlap with tenofovir by the later one. The sequence clarifies what the planned comparison is intended to address, even though the registry record does not report the resulting estimates.

The design also illustrates why the structure of a comparison matters. A single-group before-and-during sequence differs from a randomized parallel-group trial. The former can describe measurements at different times in a treatment schedule, but it does not supply a concurrent randomized control for separating treatment effects from time-related factors. Readers should distinguish the relevance of the measurement to the interaction question from the strength of causal inference supported by the design.

The endpoint’s use of a geometric mean and geometric coefficient of variation also highlights common statistical choices for pharmacokinetic data. These summaries address multiplicative scale and relative variability, while a confidence interval would be needed to assess the precision of an estimated contrast. The registry record does not report the values needed for that interpretation, making the distinction between an endpoint definition and a result especially important.

Finally, the record demonstrates the value of checking what is missing as well as what is listed. The population definition, outcome counts, and safety categories provide some context, but the primary estimates, uncertainty, missing-data handling, and multiplicity approach are not reported in the registry record. A clear description of these gaps prevents a study objective or schedule from being mistaken for evidence about the magnitude of an effect.

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 primary question is that the registry record does not report the Day 7 or Day 15 AUC values, their geometric coefficients of variation, or a contrast with uncertainty. As a result, the direction, magnitude, and precision of the primary comparison cannot be assessed from the posted results. The record’s endpoint description and sampling schedule do not substitute for outcome estimates.

The design is nonrandomized, unmasked, and single-group. The comparison is across scheduled time points rather than between randomized concurrent groups, so time-related influences cannot be separated from the effect of coadministration by design alone. The record does not report further methods that might address such influences. The primary endpoint concerns tenofovir AUC; the broader objective also refers to BI 201335 pharmacokinetics, but a corresponding numerical result is not reported in the registry record for this analysis.

The registry defines a PK analysis population using treatment exposure, evaluable observations, and absence of important protocol violations. It does not report the number included in that population, the number contributing data at each assessment, or whether all observations were paired. Missing-data methods, exclusions, sensitivity analyses, and the detailed statistical model are not reported in the registry record.

The record lists 8 outcome measures and 6 analyses but does not describe multiplicity adjustment or the statistical analysis plan. It also does not report a sample-size justification for the actual single-group design. The planning assumptions refer to an illustration based on an observed effect and equal allocation between two arms; those assumptions should not be treated as the trial’s design or as observed power. Safety categories are reported, but the record does not clarify their relationship to the sequence or report deaths.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug Drug Interaction of BI 201335 and Tenofovir — NCT01340196.
• Registry record last updated 2015-07-31; status last verified 2015-07.
• Results first posted 2015-07-31.
• 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

NCT01340196 is a completed phase 1, nonrandomized, unmasked, single-group study sponsored by Boehringer Ingelheim. The registry describes enrollment of 16 and a sequence of tenofovir once daily during the first 15 days, with BI 201335 twice daily on days 8 through 22 and a morning dose only on day 22. The official title describes healthy male and female volunteers.

The primary endpoint is steady-state tenofovir AUC0-24 on Day 7 and Day 15, summarized by geometric mean with geometric coefficient of variation. The record defines a PK analysis population but does not report the endpoint estimates, uncertainty, or a numerical comparison. It lists secondary safety outcomes and adverse event categories; serious adverse events are reported as 0 affected in each listed group, while deaths are not reported in the registry record.

The study addresses a drug-interaction question through a scheduled within-sequence comparison. Its nonrandomized single-group design and missing numerical primary results limit assessment of the size, precision, and causal interpretation of any change in exposure.