Evaluation of Safety and Tolerability of Single Rising Doses of BI 473494 in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Safety and Tolerability of Single Rising Doses of BI 473494 in Healthy Subjects (NCT03195088), a randomized phase 1 study. The primary outcome is Percentage of Participants With Drug-related Adverse Events (AEs) Analysed as Investigator Defined Drug-related AEs.

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, single-blind, parallel-group, placebo-controlled trial of single rising subcutaneous doses of BI 473494 in healthy male subjects. The official title further describes the design as partially randomised. The registry record does not explain which aspects were partially randomized, how the assignment process worked, or whether allocation was concealed. Those details should not be inferred from the general design labels.

The recorded groups were placebo matching BI 473494, BI 473494 35 μg, and BI 473494 75 μg. The arm-level counts for the primary endpoint were 4, 6, and 6, respectively. The registry record gives enrollment as 16. It does not provide a participant flow account explaining screening, assignment, treatment completion, exclusions, or the relationship between enrollment and the outcome-specific counts.

The stated primary objective was to investigate safety and tolerability after single rising doses. The secondary objective was to explore pharmacokinetics, including dose proportionality, and pharmacodynamics after single dosing. The registry record names two secondary outcomes: AUC0-tz, the area under the BI 473494 concentration-time curve from the start to the last quantifiable time point, and Cmax, the maximum measured concentration. Numerical results for these secondary outcomes are not reported in the registry record.

The listed study start was 2017-07-27, and primary completion was 2017-11-14. The current status is terminated. The reason for termination, the planned and actual study conduct, and any effect of termination on the analyses are not reported in the registry record. A sample-size justification and detailed protocol information are also not reported.

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 to participate in the trial by the trial site. The site ensured that the participants met all strictly implemented inclusion/exclusion criteria. Participants were not to be assigned to treatment groups if any one of the specific entry criteria were violated.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Treated set (TS) : The TS included all subjects who were dispensed study medication and were documented to have taken at least one dose of BI 473494.

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 dispensed study medication and were documented to have taken at least one dose of BI 473494.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Drug-related Adverse Events (AEs) Analysed as Investigator Defined Drug-related AEs, measured over From drug administration until End of trial (EOT), up to 40 days..

The primary endpoint was the percentage of participants with investigator-defined drug-related adverse events, assessed from drug administration until the end of trial, up to 40 days. The endpoint describes the proportion of participants in an arm for whom an adverse event was judged related to study medication. The record says that medical judgment considered factors such as the pattern and timing of the reaction, de-challenge or re-challenge, concomitant medication, concomitant diseases, and relevant history.

This type of endpoint is used in early-phase safety and tolerability assessment because it focuses on events that investigators consider potentially related to the study medication during the specified observation period. It is not a direct measure of pharmacokinetic exposure, pharmacodynamic activity, or clinical benefit. Nor does an investigator attribution by itself establish that the medication caused an event; it records the investigator’s judgment using the stated clinical considerations.

The registry record reports 0.0% for placebo, 0.0% for BI 473494 35 μg, and 16.7% for BI 473494 75 μg. These are arm-level percentages. No confidence intervals or formal comparison results accompany them in the registry record, so the precision of the percentages and the strength of evidence for differences between arms cannot be assessed from the posted endpoint figures alone. The outcome-specific analysis population is described as the treated set, with the definition stated in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a count-type primary endpoint: the percentage of participants with investigator-defined drug-related adverse events. It presents one value for each arm rather than a single estimate spanning a treatment-versus-control comparison. The record states that values were missing or not estimable for a two-arm comparison. As a result, there is no posted inferential estimate to interpret as the treatment effect, and an unreported comparison should not be reconstructed from the arm percentages.

What does an arm percentage communicate?

In general, an arm percentage expresses how frequently the endpoint was observed among the participants included in that arm’s analysis. It is a descriptive summary of the observed sample, not a guarantee about the event frequency in a broader population. For a sparse event outcome, the displayed percentage can be especially sensitive to the status of individual participants. The registry’s percentages are 0.0%, 0.0%, and 16.7% across placebo, 35 μg, and 75 μg, respectively. The corresponding endpoint counts are recorded as 4, 6, and 6. These values should be read as arm-level descriptions, not as evidence from a statistical test.

Why are uncertainty intervals useful?

General statistical explanation: a confidence interval communicates the range of effect estimates compatible with the observed data under a specified statistical method. It helps readers distinguish a point estimate from its precision. A narrow interval generally indicates greater precision than a wide interval, while an interval that includes values consistent with little or no difference may leave the comparative result uncertain. No confidence interval is reported for this primary endpoint in the registry record. Thus, the precision of the observed percentages and any difference among arms cannot be judged from interval estimates.

Why might sparse counts complicate comparison?

General statistical explanation: when outcomes are uncommon and group sizes are limited, conventional approximations can be unreliable, and small changes in the observed event counts can have a substantial effect on estimated percentages. Methods for sparse binary outcomes may use exact calculations or other approaches suited to low counts. Which statistical method, if any, was planned or used for this trial is not reported in the registry record. No particular method should be attributed to the sponsor based on the posted arm summaries.

What is over-dispersion, and is it reported?

General statistical explanation: over-dispersion occurs when the variability in data exceeds what a statistical model assumes. It can make standard errors too small if the model fails to account for the extra variability. It is relevant to some count models and repeated or clustered observations, but it is not something that can be assessed from these arm-level percentages alone. The registry record does not report an over-dispersion assessment or identify a model for the primary endpoint.

What does randomization contribute?

General statistical explanation: random allocation is intended to reduce systematic differences between treatment groups at the time of assignment. It does not guarantee that small groups will be balanced on every characteristic, nor does a design label reveal how allocation was carried out. The record lists randomized allocation, while the official title calls the design partially randomised. Details about the randomization procedure and the extent of partial randomization are not reported in the registry record. The single-blind designation is recorded, but the identity of the blinded parties and the practical masking procedures are not reported.

Can the record support a planned-versus-observed power interpretation?

No observed-power conclusion is supported. General statistical explanation: power is a planning quantity based on assumptions about an effect, variability, significance level, and design; it is not a useful substitute for interpreting an observed estimate and its uncertainty. Sample-size illustrations based on an observed effect, where available, are planning examples rather than the trial’s original design justification or evidence that a result is reliable. The registry record does not report a sample-size justification or a prespecified statistical plan. It lists no formal analyses, and it gives no numerical comparison estimate for this endpoint.

The registry record’s outcome is also distinct from the pharmacokinetic outcomes. AUC0-tz and Cmax are named as secondary outcomes, but their numerical results are not reported. No analysis method, transformation, model, or handling of values below quantification is reported for those outcomes. Interpretation of their distributions, dose proportionality, or relationship to adverse events is therefore not possible from the posted record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record names one primary safety endpoint and two secondary pharmacokinetic outcomes: AUC0-tz and Cmax. It does not report a multiplicity strategy, such as a hierarchy of hypotheses, adjustment for multiple testing, or designation of which secondary analyses were confirmatory. It also lists zero analyses. Without a reported statistical plan or formal analysis results, it is not possible to determine how the study intended to manage the possibility of chance findings across outcomes or dose comparisons.

Missing-data handling is not reported in the registry record. The endpoint definition identifies the treated set as subjects dispensed study medication and documented to have taken at least one dose of BI 473494, but the record does not describe how participants with incomplete follow-up, missing endpoint information, or protocol deviations were handled. It does not report whether any participants were excluded from the analysis or why. The arm counts attached to the primary result are 4, 6, and 6; a participant-flow explanation is not reported.

The analysis-population definition deserves attention because it is the stated population for the primary endpoint. The record’s wording requires documented receipt of at least one dose of BI 473494. It does not explain how this definition was applied to the placebo arm, nor does it provide a separate arm-specific population definition. No alternative intention-to-treat or per-protocol population is described. These uncertainties do not change the reported percentages, but they limit assessment of how the analyzed participants relate to the randomized groups.

Accordingly, the percentages are best treated as the registry’s descriptive outcome summaries. The record does not provide enough information to evaluate multiplicity control, missingness assumptions, or the robustness of results under alternative analysis populations.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute polyneuropathy (16.7%).

The serious adverse-event information records 0 serious events in the placebo arm, 0 in the BI 473494 35 μg arm, and 1 in the BI 473494 75 μg arm. Acute polyneuropathy is listed among the serious-event terms at 16.7%. No deaths are recorded in any arm. These figures are safety observations in the registry record; they do not establish that study medication caused an event or quantify comparative risk with statistical precision.

The separate counts for other adverse events are 0 with placebo, 2 with BI 473494 35 μg, and 1 with BI 473494 75 μg. These counts should not be conflated with the primary endpoint, which is the percentage of participants whose adverse events investigators judged to be drug-related. The serious-event listing and the primary endpoint summarize different aspects of safety. The record does not report confidence intervals or a formal statistical comparison for either set of figures.

In general, serious-event counts and investigator attribution answer different questions: seriousness describes an event category, while drug-relatedness reflects an assessment of the event’s relationship to study medication. A zero count in an arm means no event was recorded there in the registry summary; it does not demonstrate that such events cannot occur. The limited group sizes and lack of uncertainty estimates call for a descriptive, cautious reading.

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

The result describes the primary safety outcome observed during follow-up in this trial. The investigator-defined drug-related adverse-event percentage was 0.0% with placebo, 0.0% with BI 473494 35 μg, and 16.7% with BI 473494 75 μg. The record therefore reports drug-related events in the highest-dose arm and none in the other arms. It also records one serious adverse event in that arm, with acute polyneuropathy listed as a serious-event term at 16.7%. The observations are relevant to the trial’s safety and tolerability objective.

These data do not establish a causal relationship between BI 473494 and any event. Investigator-defined relatedness is a medical judgment, informed by the factors described in the registry record; it is not equivalent to proof of causation. Nor does an event appearing in an active-dose arm and not in placebo establish a treatment effect. Randomized comparisons can help assess differences, but the registry record reports no formal comparison estimate, test, or uncertainty interval for this endpoint.

The result also does not establish that BI 473494 is safe or unsafe in a broader population. The study involved healthy male subjects, single doses, and limited arm-level counts. The observation period extended from drug administration until end of trial, up to 40 days. The record does not provide information that would support conclusions about repeated dosing, long-term use, other populations, or outcomes beyond the recorded follow-up.

Finally, the registry’s listed secondary outcomes do not have numerical results in the record. The study objectives included pharmacokinetic and pharmacodynamic exploration, but the available information does not permit interpretation of exposure, dose proportionality, pharmacodynamic response, or links between these measures and adverse events. The defensible conclusion is descriptive: the posted record contains the stated safety observations, while important comparative and secondary outcome analyses are not reported.

13. Why This Trial Matters Statistically

This trial illustrates why early-phase safety results should be read as observations with limited comparative precision. The primary endpoint is a clinically reviewed, investigator-defined attribution rather than a simple count of all events. That distinction matters: the endpoint depends on judgment about timing, clinical pattern, de-challenge or re-challenge, and potential confounding factors. Readers should keep this attributed endpoint separate from the general serious-event and other-event summaries.

The arm-level pattern is visually simple but statistically difficult to interpret without an uncertainty estimate or formal comparison. The record reports no drug-related events in placebo or the 35 μg arm and 16.7% in the 75 μg arm. In limited groups, sparse outcomes can make percentages unstable. The absence of a reported comparison analysis means that the apparent difference cannot be translated into a precise estimate of the treatment effect or its uncertainty.

The design also highlights the value of a clear analysis population and participant-flow account. The treated-set definition is stated, but its application to the placebo arm and any exclusions are not explained. Randomized allocation and single masking are recorded, while the partial-randomization wording is not clarified. Such details matter when assessing whether observed group differences could reflect the allocation process or the composition of the analyzed groups.

Finally, the record names pharmacokinetic outcomes but does not report their numerical results, and it does not report the statistical plan or multiplicity approach. These gaps prevent a complete statistical assessment of the objectives. The case is a useful reminder that a registry’s descriptive safety percentages are informative observations, but they are not a substitute for analysis details, uncertainty estimates, or transparent reporting of the study’s conduct.

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 primary endpoint results are presented as arm-level percentages without confidence intervals, a formal contrast, or a reported hypothesis test. The registry record lists no analyses and indicates that values were missing or not estimable for a two-arm comparison. Consequently, neither the precision of the percentages nor the statistical evidence for differences among arms can be evaluated from the record.

The reported analysis counts are limited: 4 for placebo and 6 in each active-dose arm. The record gives total enrollment as 16 but does not provide participant flow, reasons for exclusion, or a clear account of how the treated-set definition was applied across arms. Missing-data handling and adherence to follow-up are not reported. These omissions restrict assessment of selection and attrition.

The design is described as randomized and single-blind, while the official title specifies partially randomised. The allocation procedure, concealment, identity of blinded parties, and reasons for partial randomization are not reported. The status is terminated, but the reason for termination and its implications for study completion or analysis are not reported. A sample-size justification and a prespecified analysis plan are also not reported.

The registry lists two secondary pharmacokinetic outcomes but does not report their numerical results. It does not state a multiplicity strategy or detailed methods for the primary endpoint. The study population was healthy male subjects and the dosing was single-dose; findings therefore do not address other populations or repeated dosing. These limitations mean the posted information supports a narrow descriptive reading rather than a complete comparative safety or pharmacokinetic assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of Safety and Tolerability of Single Rising Doses of BI 473494 in Healthy Subjects — NCT03195088.
• Registry record last updated 2022-07-14; status last verified 2022-06.
• Results first posted 2022-06-22.
• 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.

18. Record Summary

The registry record describes a phase 1, randomized, single-blind, parallel-group, placebo-controlled trial of single subcutaneous BI 473494 doses in healthy male subjects. It lists placebo, 35 μg, and 75 μg arms and reports enrollment of 16. The study status is terminated; the listed start was 2017-07-27 and primary completion was 2017-11-14.

The primary outcome was the percentage of participants with investigator-defined drug-related adverse events through end of trial, up to 40 days. Reported percentages were 0.0% for placebo, 0.0% for 35 μg, and 16.7% for 75 μg. The record also lists serious and other adverse-event counts, with no deaths recorded. Two pharmacokinetic outcomes are named, but numerical results are not reported.

No formal analyses, comparison estimates, uncertainty intervals, statistical plan, or multiplicity approach are reported. The available results are descriptive and do not establish a causal or statistically conclusive difference among arms.