Drug Interaction Study With BI 201335 and Methadone or Buprenorphine/Naloxone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug Interaction Study With BI 201335 and Methadone or Buprenorphine/Naloxone (NCT01637922), a non-randomized phase 1 study. The primary outcome is R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9..

2. Clinical Question

The study asked whether administering BI 201335 alongside established opioid maintenance therapy was associated with a pharmacokinetic interaction. It considered two groups: participants receiving stable methadone therapy and participants receiving stable buprenorphine/naloxone therapy. The primary endpoint focused on R-methadone exposure over a dosing interval, as described in the endpoint title. The registry record’s endpoint description instead refers to faldaprevir, so the analyte is not consistently identified in the record.

The record also lists changes from baseline in withdrawal assessments using the Objective Opiate Withdrawal Scale and the Subjective Opiate Withdrawal Scale as secondary outcomes. These measures address pharmacodynamic observations, whereas the primary endpoint is pharmacokinetic: it concerns drug concentration over time. Numerical results for these outcomes are not reported in the registry record.

3. Trial Design

This was a phase 1, completed, parallel-group study with non-randomized allocation and no masking. The registry record gives an enrollment of 34. The recorded study start was 2012-08 and primary completion was 2012-11. Boehringer Ingelheim is listed as the sponsor.

The two groups were defined by participants’ pre-existing maintenance therapy. The methadone group consisted of participants on a stable dose for at least 30 days, up to a maximum of 180mg per day. The buprenorphine group consisted of participants on stable buprenorphine/naloxone therapy for at least 30 days, up to a maximum dose of 24mg/6mg per day. The brief summary describes BI 201335 as administered daily. Specific BI 201335 dosing details are not reported in the registry record.

Because allocation was non-randomized, the groups should not be interpreted as exchangeable treatment arms. They differ by the maintenance therapy that participants were already receiving, and the record explicitly cautions that the arms are not a like-for-like control comparison. The design therefore describes observations within two therapy-defined groups rather than a randomized comparison of BI 201335 against no BI 201335.

The record lists BI 201335 in both intervention entries. It does not report the method used to assign participants to the two groups, a protocol-defined comparator, or a statistical plan. Those omissions limit what can be concluded about the intended contrast and how the analysis was planned.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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: This set included all subjects who were dispensed study medication and were documented to have taken at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9., measured over 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9.

The primary endpoint is titled “R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9.” AUC is the area under a concentration-time curve. In general, it summarizes drug exposure across a defined time interval, rather than describing concentration at just one measurement time. The registry identifies the interval as 0 to 24 hours and gives the unit as [ng*h/mL].

The record lists measurements at 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9. AUC is commonly used in pharmacokinetic assessments because overall exposure across an interval can be relevant to evaluating whether co-administration is associated with a change in drug exposure.

The endpoint is reported as a geometric mean, with geometric coefficient of variation as the dispersion measure. In general, geometric summaries are used for positive measurements that may be skewed, and the geometric coefficient of variation describes relative variability on a multiplicative scale. The registry calls the listed values unadjusted summary statistics on the original scale. However, its endpoint description says the AUC is for faldaprevir, while the title names R-methadone. This inconsistency is not resolved in the registry record, and numerical endpoint results are not reported there.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies this as a phase 1 parallel-group study with non-randomized allocation and no masking. These design features set limits on interpretation. In general, random allocation can help balance measured and unmeasured participant characteristics between groups, while masking can reduce some forms of bias in measurement or assessment. Neither feature is listed for this study. The registry also specifically states that the arms are not a like-for-like control comparison, so an across-group contrast should not be read as a randomized treatment effect.

What does AUC measure?

Area under the concentration-time curve integrates concentration measurements across a specified period. In this record the stated interval is 0 to 24 hours, with measurements scheduled at multiple times on Day 1 and Day 9. In general, this approach captures overall exposure during the interval, rather than relying on a single concentration. The title calls the endpoint R-methadone AUC, but the description calls it faldaprevir AUC. The registry record does not reconcile these labels.

Why report a geometric mean?

The endpoint uses a geometric mean and geometric coefficient of variation. In general, concentration and exposure data are positive and may have a right-skewed distribution. A geometric mean summarizes values on a multiplicative scale and is often suitable when proportional differences are more meaningful than absolute differences. A geometric coefficient of variation describes spread relative to the geometric mean. These are general statistical properties; the registry does not report the underlying participant-level data or numerical endpoint summaries needed to assess the actual distribution in this study.

What does “unadjusted” mean?

The endpoint description calls the summary statistics unadjusted and says they are on the original scale. In general, an unadjusted summary is calculated without controlling for other variables through a model. It can describe the observed data, but it does not account for possible differences in participant characteristics or other covariates. The registry record does not specify a model-based adjusted analysis, and it does not report numerical results for the primary endpoint.

What can be inferred from the group structure?

The groups reflect participants’ stable therapy: methadone or buprenorphine/naloxone. In general, non-randomized groups can differ in ways related to both group membership and outcomes. A parallel layout means the groups are followed as separate groups, but it does not itself make them comparable. Since the registry warns that these arms are not a like-for-like control comparison, their results should be described separately unless a clearly specified analysis supports a particular contrast. The method of group assignment is not reported in the registry record.

How should precision be assessed?

A confidence interval, in general, gives a range of values compatible with the data and the assumptions of the analysis. Its width communicates precision: wider intervals indicate greater uncertainty, while narrower intervals indicate greater precision. No confidence interval for the primary endpoint is reported in the registry record. A p-value, if reported, would address compatibility with a specified null model rather than convey the size or practical importance of an effect on its own. The registry record does not report a primary-endpoint p-value.

What do the planning illustrations mean?

The registry describes sample-size illustrations as planning calculations based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. For non-time-to-event outcomes, the stated convention is participants per arm; time-to-event illustrations use a total event count. These are planning illustrations, not the trial’s stated design justification and not observed power. The record does not report the trial’s own sample-size justification. No calculated sample-size values are reported in the registry record.

In general, planning calculations depend on assumptions about the effect to detect, variability, significance level, allocation and analysis method. A calculation using a fraction of an observed effect asks how many participants a hypothetical future study might require under its assumptions. It does not show that the completed study had a particular probability of detecting an effect, and it cannot substitute for an uncertainty interval around the study’s actual estimate.

What role do the secondary outcomes play?

The listed secondary outcomes are changes from baseline in the Objective Opiate Withdrawal Scale and Subjective Opiate Withdrawal Scale. These are pharmacodynamic assessments, unlike the pharmacokinetic AUC outcome. In general, separating outcome types helps distinguish concentration measurements from clinical or symptom-scale assessments. The registry record lists 17 outcome measures and 32 analyses, but does not report a complete statistical analysis plan or numerical secondary outcome results.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 17 outcome measures and 32 analyses. When a study evaluates multiple outcomes or performs multiple analyses, the chance of obtaining at least one apparently notable result can increase if each result is considered separately. In general, multiplicity methods can control or describe this issue, but the appropriate approach depends on the prespecified testing strategy and the role of each outcome. A multiplicity adjustment or testing hierarchy is not reported in the registry record.

The primary endpoint is identified, and the record also names secondary withdrawal outcomes. However, the registry does not report how those outcomes were ranked for inference, whether analyses were prespecified in a detailed plan, or whether any adjustment for multiple testing was used. Without that information and without numerical results, statistical significance across outcomes cannot be assessed.

The record describes an analysis population comprising subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. It says a subject was considered not evaluable if there was a protocol deviation relevant to relative bioavailability or the subject experienced emesis. The wording does not give further operational detail about these exclusions. The number excluded, the number contributing to each endpoint, and the handling of missing observations are not reported in the registry record.

In general, missing-data methods matter because the analysis can be affected when observations are unavailable, especially if missingness is related to participant characteristics or outcomes. The registry does not report whether missing values were imputed, omitted, or handled by another method, nor does it report sensitivity analyses. The analysis population description therefore does not establish how incomplete endpoint data were handled.

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 reports serious adverse events for each group using participants at risk and participants affected. In the methadone group, 0 of 15 participants at risk were affected by a serious adverse event. In the buprenorphine/naloxone group, 0 of 19 participants at risk were affected by a serious adverse event. These are the counts recorded in the registry, not evidence that an event could not occur or that the study ruled out uncommon harms.

For other adverse events, 12 of 15 participants at risk were affected in the methadone group, and 18 of 19 were affected in the buprenorphine/naloxone group. The registry does not provide event terms alongside these aggregate counts in the listed information, so the specific events and their severity cannot be described from these figures alone.

Death counts are not reported in the registry record. The serious adverse event term list is empty; this should be read as no terms listed in that record, alongside the reported zero affected counts, rather than as additional detail about event types. These group counts are descriptive, and the non-randomized design does not support attributing differences in adverse-event counts to BI 201335.

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

The study addresses a relevant statistical problem: how to characterize drug exposure when BI 201335 is administered to participants receiving different forms of stable opioid maintenance therapy. A concentration-time endpoint can summarize exposure across a dosing interval, while withdrawal scales provide separate pharmacodynamic assessments. These endpoints answer different kinds of questions and should not be conflated.

The registry record does not report numerical primary endpoint results, so it does not establish the direction or size of an AUC change between Day 1 and Day 9. It also does not report numerical results for the secondary withdrawal outcomes. Accordingly, the posted information cannot quantify a pharmacokinetic interaction or describe the precision of an estimated effect. This is a limitation of what is reported, not evidence that the measured outcomes were unchanged.

The groups were non-randomized and defined by their maintenance therapy. They are not a like-for-like control comparison. Their descriptive results should therefore not be interpreted as if participants had been randomly assigned to methadone or buprenorphine/naloxone, or as if one group represented an untreated control. The registry record does not provide a randomized contrast that would support such an interpretation.

The safety figures report zero participants affected by serious adverse events in both groups, along with other adverse events in both groups. These observations describe the recorded counts only. They do not establish causation, rule out uncommon events, or determine how the therapies compare in safety.

The endpoint label inconsistency also constrains interpretation: the title names R-methadone, while the endpoint description names faldaprevir. Until that is clarified in the registry record, the intended measured analyte is not unambiguous. The findings should be read as a record of study design and outcome definitions, not as a complete account of efficacy, safety, or clinical effect.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of how pharmacokinetic questions can arise in a population already receiving stable therapy. AUC summarizes exposure across a dosing interval, and repeated assessment on Day 1 and Day 9 gives the endpoint a time-specific structure. The endpoint is not a single concentration measurement, and its interpretation depends on the identity of the analyte and the completeness of the reported summaries.

The design also illustrates why the label “parallel group” does not by itself imply a controlled treatment comparison. Here, participants were grouped according to established methadone or buprenorphine/naloxone therapy, allocation was non-randomized, and the registry cautions against treating the arms as like-for-like controls. Statistical reporting should preserve that distinction rather than imply that group differences isolate an effect of BI 201335.

For biostatisticians and clinical researchers, the record highlights the importance of alignment between an endpoint title and its measurement description. It also shows why estimates and uncertainty measures matter: without numerical endpoint results, a defined outcome alone cannot convey the magnitude, direction, or precision of an observed effect. Similarly, counts of adverse events can describe what was recorded but require context before they can support comparative interpretation.

The record’s planning assumptions are another useful reminder that sample-size illustrations are not evidence of observed power. Such calculations are conditional on assumptions and intended for planning, while the completed study’s actual estimates and uncertainty must be reported separately. The registry record does not provide the primary endpoint results needed for that assessment.

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 most direct limitation is that numerical results for the primary endpoint are not reported in the registry record. The record also does not provide numerical results for the listed withdrawal outcomes, confidence intervals, or primary-endpoint p-values. The direction, size, and precision of the outcome estimates therefore cannot be evaluated from the posted information.

The primary endpoint is described inconsistently. Its title identifies R-methadone, while its description says the AUC is for faldaprevir. The record does not clarify whether this reflects a labeling error or another issue, so the substance underlying the endpoint is ambiguous.

The study used non-randomized allocation, no masking, and groups defined by pre-existing maintenance therapy. The registry explicitly states that the arms are not a like-for-like control comparison. These design characteristics limit interpretation of across-group contrasts, and the method of group assignment is not reported in the registry record.

The record does not report the detailed statistical analysis plan, a sample-size justification, multiplicity procedures, missing-data methods, or sensitivity analyses. It describes an evaluable analysis population but does not give endpoint-specific participant counts or the number excluded. The criteria involving protocol deviations relevant to relative bioavailability and emesis are not explained in further detail.

Safety information is limited to aggregate counts in the listed record. Specific terms for other adverse events, death counts, and additional context about timing or attribution are not reported in the registry record. These limitations mean the available safety counts should be treated as descriptive rather than as a complete comparative safety analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug Interaction Study With BI 201335 and Methadone or Buprenorphine/Naloxone — NCT01637922.
• Registry record last updated 2015-08-03; status last verified 2015-07.
• Results first posted 2015-08-03.
• 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 evaluated BI 201335 in parallel groups of participants on stable methadone or buprenorphine/naloxone therapy. Allocation was non-randomized and masking was absent. The registry identifies an AUC endpoint for Day 1 and Day 9, but its title and description name different analytes. Numerical results for the primary endpoint and the listed withdrawal outcomes are not reported in the registry record.

The safety record lists zero serious adverse event-affected participants in each group and reports other adverse events in both groups. The group structure does not constitute a like-for-like control comparison. The registry does not report a detailed statistical plan, multiplicity approach, or missing-data method.