A Study in Healthy Men to Test How Zongertinib is Taken up in the Body When Taken With or Without Food: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men to Test How Zongertinib is Taken up in the Body When Taken With or Without Food (NCT06075277), a randomized phase 1 study. The primary outcome is Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).

2. Clinical Question

The crossover design means participants received both food conditions in separate periods, with randomized treatment sequence. The two sequences were fed then fasted and fasted then fed. The focus is relative bioavailability: how the measured exposure under one administration condition compares with exposure under the other. This is a pharmacokinetic question in healthy participants, not a comparison of clinical outcomes in people being treated for a disease.

3. Trial Design

This was a Phase 1, randomized, open-label, two-way crossover trial in healthy men. The registry records enrollment of 16 participants and a completed status. The study began on 2023-10-19, and primary completion was recorded as 2024-01-02. The sponsor was Boehringer Ingelheim.

Participants received zongertinib as film-coated tablets in both conditions. Each administration was a single oral dose of 240 mg, described as four 60 mg tablets. In the fed condition, dosing followed a high-fat, high-calorie meal. In the fasted condition, dosing followed an overnight fast of at least 10 hours. The registry describes two treatment sequences: fed followed by fasted, and fasted followed by fed. Random allocation to sequence helps avoid assigning every participant to the same order, while the within-participant comparison allows exposure under the two conditions to be compared within the crossover structure.

The trial was open-label, so masking was not used. The registry identifies the primary endpoint as AUC from time zero to the last quantifiable data point, abbreviated AUC0-tz. Blood sampling was scheduled within 3 hours before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours following administration. These measurements support calculation of a concentration-time exposure measure.

The registry record does not report the washout interval, the rationale for the enrollment target, or whether any participants failed to complete both periods. It also does not give a fuller account of adherence or protocol deviations beyond the stated analysis-set description. Those details should not be inferred from the crossover design alone.

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

Period 1

Washout Period

Period 2

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic parameter analysis set (PKS): all subjects who were randomised and received at least one dose of trial medication and who provided at least one pharmacokinetic (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 treated set includes all subjects who were treated with at least one dose of trial drug.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz), measured over Within 3 hours before Zongertinib administration, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours following administration..

The primary endpoint was the area under the plasma concentration-time curve of zongertinib from time zero to the last quantifiable data point, AUC0-tz. Its unit was hour*nanomol/Liter (h*nmol/L). AUC represents exposure accumulated over time: it incorporates concentrations measured at multiple sampling times rather than relying on a single concentration measurement.

The endpoint is useful for a relative bioavailability comparison because the study asks whether exposure differs when the same oral dose is taken with food or while fasted. The registry describes sampling within 3 hours before administration and at multiple times through 168 hours after administration. The last quantifiable data point marks the end of the observed interval used for this endpoint; it is distinct from AUC0-∞, which is listed as a secondary outcome and extends the exposure measure by extrapolation beyond observed concentrations.

The analysis description states that pharmacokinetic endpoints were log-transformed before fitting an analysis of variance model, and that adjusted geometric means and geometric standard errors were calculated. Results were then back-transformed to the original scale, with point estimates and 90% confidence intervals. The reported primary comparison is a ratio of adjusted geometric means, which expresses fed-condition exposure relative to fasted-condition exposure. It does not directly describe symptoms, treatment benefit, or long-term safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous and positive: AUC0-tz measures plasma exposure over time. The registry describes an analysis of variance model applied after natural-log transformation of the pharmacokinetic endpoints. A log transformation is commonly used for exposure measures because values are positive and comparisons are often naturally expressed as relative changes. This is general statistical context, not an additional description of unreported model terms.

Why analyze the logarithm of exposure?

On the logarithmic scale, multiplicative differences in the original exposure values become additive differences. This makes a treatment comparison on that scale suitable for back-transformation into a ratio of geometric means. A geometric mean is a measure of central tendency formed through the log scale; it is not the same as an ordinary arithmetic average. In this trial, the registry specifically reports adjusted geometric means and a ratio of those means.

Adjustment indicates that the model estimates treatment-condition means while accounting for terms included in that model. The registry identifies an analysis of variance model, but the complete model specification and its terms are not reported in the registry record. The treatment ratio should therefore be interpreted as the model-based adjusted comparison described in the endpoint record, without assuming which additional covariates or period and sequence terms were included.

What does the ratio express?

The reported ratio compares the adjusted geometric mean under fed dosing with the adjusted geometric mean under fasted dosing. It is expressed as a percentage. A ratio is useful for relative bioavailability because the scientific question concerns exposure under one condition relative to exposure under another, rather than only the difference between two raw-scale means. The reported estimate is 126.64%, and its 90% confidence interval is 112.09% to 143.08%.

A confidence interval is an uncertainty interval produced by a statistical procedure. In general, repeated use of a procedure with the same confidence level would capture the underlying parameter at that level over repeated studies under the procedure’s assumptions. It is not a probability statement about the fixed parameter after observing this particular interval, and it is not a prediction interval for individual participants. The 90% level is the level reported for this analysis; the registry record does not report a corresponding p-value.

How does crossover allocation matter?

In a crossover study, each participant receives both conditions in different periods, while randomized sequence determines which condition comes first. This design can support a within-participant comparison, because each participant contributes information under both conditions. Such comparisons can account for stable differences between participants, but they also require appropriate handling of period and sequence structure and depend on assumptions about effects carrying over between periods. The record identifies the trial as a two-way crossover but does not report the washout interval or the full statistical model specification. It is therefore not possible to assess those design details from the registry record alone.

The trial was open-label. For a pharmacokinetic endpoint measured from plasma concentrations, awareness of the food condition does not change the numerical definition of AUC, but open-label status remains part of the design and may matter for procedures or decisions surrounding the study. The registry record does not describe whether laboratory or analysis personnel were masked.

What is the role of the sampling schedule?

Plasma measurements were scheduled within 3 hours before administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours following administration. Repeated concentration measurements allow the exposure curve to be characterized over the observed period. AUC0-tz uses the interval from time zero to the last quantifiable data point. The listed secondary endpoint, AUC0-∞, extends the measure to infinity through extrapolation; the registry record does not provide its result in the posted secondary outcomes summary.

Geometric standard error is reported in the endpoint description as a measure used in calculating the geometric least-squares means. It describes uncertainty around an estimated geometric mean, rather than the spread of individual observations in the same way as a standard deviation. The primary comparison is accompanied by a confidence interval, which is the more direct summary of uncertainty for the ratio.

General statistical context: crossover models can include terms that reflect treatment, period, and sequence, but the record does not state the complete model formula. Neither a particular model structure beyond the stated analysis of variance on the log scale nor additional assumptions should be attributed to this analysis without documentation.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison as a ratio of adjusted geometric means: 126.64% for fed relative to fasted dosing, with a 90% confidence interval of 112.09% to 143.08%. The endpoint description states that the adjusted geometric means and geometric standard errors were calculated using an analysis of variance model on log-transformed pharmacokinetic endpoints, then back-transformed to the original scale.

The arm-level values are 59460.0 for fed dosing and 46950.0 for fasted dosing. Those values are not enough to reproduce the reported adjusted ratio and its confidence interval, because the posted analysis is model-based and the complete model specification and underlying participant-level measurements are not reported in the registry record. No separate unadjusted re-calculation of the primary comparison is stated in the registry record. Accordingly, the sponsor’s reported adjusted estimate is the available inferential result; the arm-level values provide context but should not be treated as a replacement for it.

The record reports no p-value for this comparison. It also does not report an equivalence margin or other decision criterion. The result can therefore be described as an estimated relative exposure with an associated confidence interval, without asserting whether it meets a threshold not documented in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 3 analyses, while 1 secondary outcome is listed in the posted results summary. That secondary outcome is AUC0-∞. The primary endpoint is AUC0-tz. The registry record does not explain whether the listed outcomes correspond one-to-one with analyses, whether additional outcomes were planned but not posted, or how the outcome list relates to any prespecified statistical hierarchy.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or whether the primary endpoint was the sole confirmatory comparison. When several endpoints or comparisons are examined, multiplicity procedures may be used to control the chance of false-positive findings across the family of tests. This is general statistical context; no particular procedure should be assumed for this trial. The absence of a reported multiplicity method means the record does not establish how multiple statistical questions were handled.

The primary endpoint description names a pharmacokinetic parameter analysis set. It includes participants who were randomized, received at least one dose, and provided at least one primary or secondary pharmacokinetic endpoint that was not excluded because of a protocol deviation relevant to the evaluation. The remainder of that population description is truncated in the registry record. The record does not provide a complete participant flow, the number included in the primary analysis, or a detailed account of missing endpoint data.

Missing pharmacokinetic measurements can affect the ability to estimate an exposure curve and the endpoint derived from it. The registry record does not describe imputation, handling of incomplete concentration profiles, or sensitivity analyses for missing data. It also does not report whether any observations were excluded beyond the reference to relevant protocol deviations in the analysis-set definition.

The randomized crossover design makes the sequence and period structure relevant to analysis, but the record does not report the complete model terms or a detailed account of how incomplete periods were handled. These omissions limit independent assessment of the analysis population and the robustness of the result. They do not justify assuming that data were missing or that a particular corrective method was used.

12. 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 reports 0 serious adverse events in the fed treatment group and 0 in the fasted treatment group. Deaths are reported as 0 in each group. For other adverse events, 7 affected participants are reported in each treatment group, with 16 at risk in each group.

These figures should be read as descriptive safety counts from this trial, not as a formal comparison of risk. The study was a crossover, so the same participant could receive both treatment conditions; the group counts should not be added to infer a total number of distinct participants. The record does not provide event terms for the other adverse events in the posted safety summary, nor does it describe severity, timing, or whether an event occurred in one or both periods for an individual.

Zero reported serious adverse events means none were recorded in the relevant treatment-group summaries; it does not establish that serious events are impossible or that a condition has no safety risk. The trial enrolled healthy participants and was designed around pharmacokinetic exposure after single doses. Its safety counts are therefore limited to the trial setting and should not be generalized beyond the population and conditions studied.

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

The central statistical finding is a higher adjusted geometric mean AUC0-tz under fed dosing than under fasted dosing, expressed as a fed-to-fasted ratio of 126.64%. The 90% confidence interval, from 112.09% to 143.08%, summarizes the uncertainty in that estimated relative exposure under the reported analysis. The estimate concerns plasma exposure following a single 240 mg dose of the intended commercial formulation in healthy men under the meal and fasting conditions described.

This result is not a direct measure of clinical benefit or harm. AUC is a pharmacokinetic endpoint, not a patient-centered outcome, and the registry record does not report outcomes such as symptom change or disease control. The trial also does not establish what exposure differences mean for a clinical decision, because the record does not state a prespecified acceptable range or a link between the observed exposure and clinical outcomes.

The findings should not be extended automatically to other populations, dosing regimens, formulations, or meals. The trial was a single-dose comparison in healthy participants. It does not answer whether repeated use produces the same relative exposure, how exposure behaves in people with a condition, or whether other food conditions produce similar results.

The confidence interval communicates uncertainty around the group-level ratio, not the range of individual responses. The registry record does not provide individual concentration profiles or a distribution of participant-level treatment contrasts. Nor does it provide enough detail to independently reproduce the adjusted model-based result. The reported comparison is therefore most informative as a summary of relative pharmacokinetic exposure under the studied conditions, with its precision described by the confidence interval.

In short, the record supports a descriptive statistical conclusion about measured exposure in this trial. It does not alone establish clinical importance, a dosing recommendation, or the result of applying an unreported bioequivalence criterion.

14. Why This Trial Matters Statistically

This trial illustrates how a clinical pharmacology question can be framed as a relative comparison of exposure rather than a comparison of clinical outcomes. The same drug and dose were administered under fed and fasted conditions, and the primary endpoint integrated plasma concentrations over time. Reporting a ratio of adjusted geometric means aligns the statistical summary with that relative-exposure question.

The crossover design is also statistically important. Each participant received both conditions in separate periods, and treatment sequence was randomized. In general, this structure can make within-participant information useful by reducing the influence of stable between-participant differences. At the same time, it makes the period and sequence structure relevant, and interpretation depends on suitable conduct and analysis. The registry record identifies the crossover design but does not supply enough detail to evaluate all of those features.

The example also shows why the point estimate and confidence interval should be read together. The ratio gives the estimated direction and scale of the relative exposure, while the interval conveys uncertainty around that estimate. Neither alone answers whether the difference matters clinically. That judgment requires a relevant decision criterion and context, neither of which is reported in the registry record.

Finally, the result shows the distinction between a pharmacokinetic finding and a therapeutic conclusion. Exposure measurements can inform understanding of drug absorption, but a single-dose study in healthy participants does not by itself establish patient outcomes. Statistical interpretation is strongest when the estimand, analysis scale, population, and limitations are kept explicit.

15. 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 gives a concise account of the trial but leaves several details needed for independent appraisal unreported. It does not report the rationale for the enrollment target, the planned precision or power, or a sample-size justification. No such rationale should be inferred from the observed estimates.

The record identifies a two-way crossover and the treatment sequences, but does not report the washout interval, the complete analysis model, or how period and sequence effects were handled. The description states that an analysis of variance model was fitted on the logarithmic scale, but its full specification is not reported. The record also does not state whether laboratory personnel or analysts were masked in this open-label study.

The analysis-set definition is incomplete in the registry record. It refers to randomized participants who received at least one dose and provided at least one eligible pharmacokinetic endpoint, subject to exclusion for relevant protocol deviations, but the full description is truncated. The number included in the primary analysis, participant flow through both periods, and handling of missing concentration measurements are not reported. These details matter when assessing how closely the analysis population follows the randomized population and how incomplete profiles may affect AUC estimates.

The registry reports the primary adjusted ratio and confidence interval but does not report a p-value, a bioequivalence margin, or another decision threshold. The secondary outcome AUC0-∞ is listed, but its result is not included in the posted secondary outcomes summary. The registry also does not report a multiplicity strategy or a detailed account of protocol deviations.

External interpretation is limited by the setting: healthy male participants, a single dose, one formulation, and the specified fed and fasted conditions. The findings do not directly characterize repeated dosing or other populations and administration conditions. The safety summary is similarly limited, with no event terms for the other adverse events described in the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study in Healthy Men to Test How Zongertinib is Taken up in the Body When Taken With or Without Food — NCT06075277.
• Registry record last updated 2025-09-22; status last verified 2025-09.
• Results first posted 2025-09-22.
• 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.

19. Record Summary

NCT06075277 is a completed, randomized, open-label, Phase 1 two-way crossover trial in healthy men. The registry records enrollment of 16 participants and evaluates a single 240 mg oral dose of zongertinib under fed and fasted conditions. The fed condition followed a high-fat, high-calorie meal; the fasted condition followed an overnight fast of at least 10 hours.

The primary endpoint was plasma AUC0-tz. The reported adjusted geometric mean ratio for fed versus fasted dosing was 126.64%, with a 90% confidence interval of 112.09% to 143.08%. The endpoint was analyzed using an analysis of variance model on the logarithmic scale, with estimates back-transformed to the original scale.

The registry reports 0 serious adverse events and 0 deaths in each treatment group, and 7 participants affected by other adverse events in each group. Important details, including the full model specification, washout interval, complete analysis population, missing-data handling, and any decision threshold, are not reported in the registry record.