A Study in Healthy Men and Women to Test Whether BI 1358894 Influences the Amount of Bupropion in the Blood: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men and Women to Test Whether BI 1358894 Influences the Amount of Bupropion in the Blood (NCT04899674), a na phase 1 study. The primary outcome is Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).

2. Clinical Question

In practical statistical terms, this is a pharmacokinetic question about relative exposure under two treatment conditions. The same fixed sequence places the reference condition before the test condition. That makes the order of conditions important when interpreting any comparison: treatment condition and period are not separated by randomized sequencing. The record does not report a numerical estimate of the relative exposure or its precision, so the direction and magnitude of any observed difference cannot be described from the registry record.

3. Trial Design

This was a Phase 1, open-label, two-period fixed-sequence trial in healthy volunteers. The registry lists an enrollment of 18, no masking, no randomized allocation, and a single-group model. Participants received bupropion alone in the reference condition and then BI 1358894 with bupropion in the test condition. The stated objective was to investigate the relative bioavailability of a single bupropion dose between those conditions.

The design uses two conditions in sequence rather than assigning participants to separate concurrent groups. In general, comparing conditions within the same participant can reduce the influence of stable differences between people. But a fixed order does not randomize or counterbalance period. Any change over time, including a period effect, would occur alongside the change in treatment condition. The registry record does not report how such effects were addressed in the analysis.

The primary outcome concerns bupropion concentration in plasma over time. The record describes planned sampling within 3 hours before bupropion and at specified times through 120 hours for the reference condition, and within 0.5 hours before and at specified times through 120 hours for the test condition. The endpoint timeframe is stated as up to 120 hours after bupropion administration. Further details of the timeframe are not reported in the registry record.

The trial status is completed. The registry lists its start as 2021-06-30 and primary completion as 2021-09-02. The record does not report a randomized control group, masking, or a parallel-group comparison. It also does not report the rationale for the enrollment target, detailed eligibility criteria beyond healthy volunteers, or the planned handling of period effects.

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: All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Reference

Test

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.

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: Treated set (TS): The TS included all subjects who were randomised and treated with at least 1 dose of trial drug.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz), measured over Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description)..

The primary endpoint is the area under the plasma concentration-time curve for bupropion from time zero to the last quantifiable data point, abbreviated AUC0-tz. It summarizes bupropion exposure across the observed concentration profile rather than describing a concentration at just one sampling time. Its unit is hours * nanomole/Liter, and the registry identifies the reported parameter as a geometric least-squares mean with standard error as the dispersion measure.

As general pharmacokinetic context, an area under a concentration-time curve combines information about concentrations and the time over which they are observed. It is used to characterize overall exposure. A comparison of this measure between the reference and test conditions can address the trial’s relative-bioavailability question, subject to the design and analysis used. AUC0-tz ends at the last quantifiable data point, so its definition depends on the observed concentration profile and the specified sampling schedule.

The registry record describes sampling through 120 hours after bupropion administration and gives different pre-dose windows for the two conditions. It does not report the endpoint’s numerical estimates, a treatment contrast, a confidence interval, or a p-value. Consequently, the endpoint definition explains what was to be measured, but the record does not establish how large or precise the observed comparison was.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUC measure?

The primary endpoint is AUC0-tz, the area under the plasma concentration-time curve from time zero to the last quantifiable data point. As general statistical and pharmacokinetic context, a concentration-time curve represents measured concentrations across sampling times, and its area summarizes exposure across that observed interval. This differs from comparing concentrations at a single time point, which may not capture the full profile. The endpoint’s interval and sampling schedule matter because the summary is based on the observations available over time.

The registry identifies the parameter as a geometric least-squares mean. In general, a least-squares mean is an estimate derived from a statistical model, and a geometric summary is suited to data analyzed on a multiplicative scale. These labels alone do not reveal the model, any transformation, or the comparison estimate. The statistical model and transformation details are not reported in the registry record.

What does the standard error describe?

The registry lists standard error as the dispersion measure for the geometric least-squares mean. In general, a standard error describes the sampling uncertainty of an estimate under the model and data used; it is not the same as the spread of individual participant measurements. It can help characterize precision, but it is most interpretable alongside the estimate and, commonly, a confidence interval. Neither the primary estimate nor its standard error is reported as a numerical result in the registry record. A confidence interval for the primary comparison is also not reported.

How does the sequence affect interpretation?

This trial has a single group and a fixed sequence, with bupropion alone before BI 1358894 with bupropion. In general, a within-participant comparison can account for stable characteristics that differ between participants. However, the fixed order means that period and treatment condition change together. If outcomes vary over time for reasons unrelated to the condition, that variation may complicate interpretation. A randomized sequence can help balance order effects across conditions, but the registry does not describe such randomization. It also does not report the analysis used to address period effects or other design features.

What is known about analysis populations?

The primary endpoint population is defined as the pharmacokinetic parameter analysis set. It includes treated participants who provided at least one primary or secondary pharmacokinetic endpoint, except when they were excluded because of a protocol deviation relevant to pharmacokinetic evaluation or because of pharmacokinetic non-evaluability. This definition clarifies which participants were eligible for that analysis. The number included in the set, the number excluded, and reasons for any exclusions are not reported in the registry record.

In general, analysis populations can differ from enrollment because not every enrolled participant necessarily contributes evaluable data to every endpoint. The enrollment count of 18 therefore does not by itself state the number analyzed for AUC0-tz. The record does not report how missing concentration measurements were handled, whether any values were imputed, or how incomplete profiles affected endpoint calculation.

What do the planning assumptions mean?

The sample-size assumptions describe a planning illustration computed from the observed effect, not the trial’s own design. The listed assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. General interpretation: such an illustration asks how a hypothetical design might perform under stated assumptions. It is not the trial’s observed power, and it should not be confused with the evidence for the actual comparison. The record does not report the trial’s sample-size justification or the detailed statistical plan used to analyze the fixed-sequence design.

For planning calculations, a significance level sets a decision threshold under a specified statistical procedure, while power describes the probability of detecting an effect under stated assumptions. A normal approximation uses a simplified distributional model. These concepts explain the illustration’s assumptions; they do not establish that the trial used those methods for its primary analysis. The registry record does not report the primary analysis method, any interim analyses, or a multiplicity adjustment.

What is missing for a complete statistical reading?

The registry lists three outcome measures and three analyses, but it names only the primary AUC0-tz endpoint and one secondary AUC endpoint, AUC0-∞. The remaining outcome details are not reported in the registry record. The statistical methods, numerical endpoint estimates, treatment contrast, confidence intervals, p-values, and missing-data procedures are also not reported. Without those details, the design and endpoint can be described, but the statistical strength and precision of the primary comparison cannot be assessed from the record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and three analyses. It names AUC0-tz as the primary endpoint and lists AUC0-∞ as a secondary endpoint. The details of the remaining outcome measures are not reported in the registry record. The record does not state whether the analyses formed a prespecified family of tests, whether any multiplicity adjustment was planned, or how results across outcomes were to be interpreted.

Multiplicity matters in general when several outcomes or statistical tests are considered, because the chance of at least one apparently notable result can increase as the number of tests grows. Different approaches may control that risk or prioritize an endpoint in advance. The registry record does not report a multiplicity strategy, so no claim about adjustment or control of error across analyses can be made.

The primary analysis population is defined as the pharmacokinetic parameter analysis set. It includes treated participants with at least one primary or secondary pharmacokinetic endpoint, unless excluded for a relevant protocol deviation or pharmacokinetic non-evaluability. The number included in that set and the reasons for any exclusions are not reported in the registry record. Enrollment of 18 is not a substitute for the analysis-set count.

Missing-data handling is not reported in the registry record. It does not state how missing concentration measurements or incomplete pharmacokinetic profiles were handled, whether any imputation was used, or how non-evaluable profiles were treated beyond the analysis-set exclusion definition. These omissions limit assessment of whether the analyzed data could differ systematically from the data that would have been available under complete follow-up.

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 lists serious adverse event figures separately for bupropion, BI 1358894, and BI 1358894 with bupropion. In the bupropion group, 18 were listed at risk and 0 were affected by serious adverse events. For BI 1358894, 18 were listed at risk and 0 were affected. For the combination, 17 were listed at risk and 0 were affected. The record lists 0 deaths in each group.

For other adverse events, the registry lists 18 at risk and 4 affected in the bupropion group, 18 at risk and 9 affected in the BI 1358894 group, and 17 at risk and 3 affected in the combination group. These are the registry’s listed counts; they are not a randomized comparison. The sequence of conditions and the different at-risk counts should be kept in mind when reading them. The figures alone do not establish that a condition caused an event or support a comparative safety conclusion.

The record does not provide further detail on the event terms, severity categories beyond the serious-versus-other distinction, timing, duration, or relatedness assessment. No serious adverse event terms are listed. The counts describe what the registry reports and should not be interpreted as proof that an unlisted event did not occur outside the recorded data.

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

This trial’s stated purpose was to examine the relative bioavailability of a single bupropion dose when given alone and when given with BI 1358894. The primary endpoint, AUC0-tz, is an exposure summary based on bupropion concentrations in plasma over time. The registry describes the endpoint, sampling windows, and the fixed sequence of treatment conditions.

What the registry record does not provide is the primary endpoint’s numerical result. It does not report the geometric least-squares mean for either condition, a treatment contrast, an interval estimate, or a p-value. As a result, the record does not permit a description of the observed direction, size, or precision of the exposure comparison. It also does not support a conclusion that the combination increased, reduced, or left unchanged bupropion exposure.

The fixed order is relevant to what the comparison can mean. Bupropion alone was given first, followed by the combination condition. Unlike a randomized parallel-group study, the conditions were not assigned to separate groups in a like-for-like concurrent comparison. Period and treatment condition therefore cannot be treated as independently randomized based on the information in the registry. The record does not describe how the analysis handled this feature.

The listed safety figures include no serious adverse events or deaths in the recorded groups, alongside counts for other adverse events. These counts should be read as descriptive registry data, not as a causal comparison or as a complete characterization of safety. The record does not report detailed event terms or relatedness assessments.

The appropriate interpretation is therefore narrow: the registry documents a completed Phase 1 pharmacokinetic study, its treatment sequence, endpoint definition, analysis-set criteria, and adverse-event counts. It does not report the primary pharmacokinetic result or enough analysis detail to assess its statistical precision. The stated objective should not be mistaken for a reported finding.

13. Why This Trial Matters Statistically

This study illustrates why design details are central to interpreting pharmacokinetic comparisons. AUC0-tz compresses a series of plasma concentrations into an exposure measure, but that summary is meaningful only alongside its estimation method, uncertainty, and the conditions under which the samples were collected. The registry identifies the endpoint and its planned sampling period, yet does not report the resulting estimate or its precision.

The fixed-sequence arrangement also matters statistically. A within-participant design can reduce the influence of stable differences among people, a useful feature in general. But when every participant receives the reference condition before the test condition, order and treatment condition are linked. Any period-related change could complicate the contrast. The registry’s description of a fixed sequence is therefore essential context and should not be read as a randomized comparison.

The record also demonstrates the difference between an analysis-population definition and an analysis result. It defines the pharmacokinetic parameter analysis set, but does not state its size or report endpoint estimates. Similarly, planning assumptions are not evidence that the trial had a particular observed power. The listed assumptions describe an illustration, not the trial’s design justification or result.

Finally, registration details can establish what the study set out to assess without supplying the evidence needed to judge the estimate. For this trial, the objective and endpoint are clear, while the primary numerical comparison and key statistical procedures are not reported in the registry record. Keeping that distinction explicit prevents a study aim from being mistaken for a finding.

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 does not report the primary endpoint estimates, the treatment contrast, confidence intervals, or p-values. This prevents assessment of the observed magnitude, direction, or precision of the pharmacokinetic comparison. The record also does not report the statistical model, transformation details, or the way the fixed sequence and possible period effects were addressed.

The trial used a fixed sequence, with bupropion alone before BI 1358894 with bupropion. Since treatment condition and order are linked, a condition comparison may be difficult to distinguish from changes associated with period. The record does not describe methods to address this concern. It also does not describe a randomized treatment sequence or a parallel control group.

Although enrollment is listed as 18, the number included in the primary pharmacokinetic analysis set is not reported. The record defines that set but does not give its size, exclusions, or participant-level data availability. Missing concentration data handling, imputation, and the treatment of incomplete profiles are not reported.

The registry lists three outcome measures and three analyses, but details of all outcomes and any multiplicity approach are not reported. The planning assumptions are explicitly an illustration rather than the trial’s own design; the record does not report the sample-size justification. Safety reporting is also limited: the record provides counts of serious and other adverse events and deaths, but does not list event terms or relatedness assessments. These gaps restrict interpretation to the study’s stated objective, design, endpoint definition, and listed counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study in Healthy Men and Women to Test Whether BI 1358894 Influences the Amount of Bupropion in the Blood — NCT04899674.
• Registry record last updated 2025-02-24; status last verified 2025-02.
• Results first posted 2025-02-24.
• 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

NCT04899674 is a completed Phase 1, open-label, two-period fixed-sequence trial sponsored by Boehringer Ingelheim. It enrolled 18 healthy volunteers. The reference condition was a single dose of bupropion alone, followed by the test condition of BI 1358894 with bupropion.

The primary endpoint was bupropion AUC0-tz, reported as a geometric least-squares mean with standard error as the dispersion measure. The registry defines the pharmacokinetic analysis population but does not state its size. It lists AUC0-∞ as a secondary outcome. The primary endpoint result and key analysis details are not reported in the registry record.

The registry lists 0 serious adverse events and 0 deaths in each recorded group, with other adverse-event counts of 4 for bupropion, 9 for BI 1358894, and 3 for the combination. These counts are descriptive and do not establish causation or a randomized comparison.