A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated (NCT04537897), a randomized phase 1 study. The primary outcome is Percentage of Participants With Drug-related Adverse Events.

2. Clinical Question

3. Trial Design

This completed phase 1 study evaluated safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 474121 in healthy young and elderly male and female participants. It also included an evaluation of a midazolam interaction in young healthy participants. The registry lists a randomized, double-blind, parallel-group design for the main study and describes the midazolam component as nested, open, fixed-sequence, and intra-individual. These design features matter when interpreting the results: the placebo-controlled dose groups and the midazolam component do not represent an identical type of comparison.

Part A enrolled young participants into placebo or BI 474121 groups receiving 2.5mg, 5mg, 10mg, 20mg, or 30mg once daily for 14 days. Part B enrolled elderly participants into placebo or BI 474121 groups receiving 5mg or 10mg once daily for 14 days. The listed dose schedules were oral. For specified Part A groups, the registry also describes oral midazolam on Day -1, 1, and 14. The brief description states that midazolam was used to assess interaction, while the detailed protocol description characterizes that component as a fixed-sequence intra-individual comparison.

The registry reports enrollment of 70 and identifies the study as completed. The recorded start date is 2020-10-06 and the primary completion date is 2021-10-07. These are record-level design and study-status details; they do not indicate the number of participants contributing to each endpoint. The group-specific denominators reported for the primary endpoint differ across arms, so interpretation should use those denominators rather than infer a common group size from overall enrollment.

The age categories, healthy-participant setting, short dosing period, and distinct study components delimit what these results can describe. The record does not report a longer-term follow-up beyond the endpoint timeframes stated, nor does it report the trial’s original sample-size justification or statistical design assumptions. The posted data therefore support a descriptive reading of the listed outcomes, while broader claims about other populations, longer exposures, or unreported comparisons are outside what the record establishes.

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: Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated set (TS): The TS included all subjects who were randomised and treated with at least 1 dose of trial drug.

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.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Drug-related Adverse Events, measured over For Midazolam: From first dose of midazolam (on Day -1) until first dose of BI 474121/Placebo, up to 1 day. Other groups: From first dose of BI 474121/Placebo until last dose+7 days of residual effect period, up to 21 days..

The primary endpoint is the percentage of participants with drug-related adverse events. It is a binary participant-level summary: each participant is classified according to whether a drug-related event was reported within the applicable observation period, and the result is expressed as a percentage of participants. The registry says medical judgment was used to assess the relationship between study medication and adverse events, considering factors such as the reaction pattern, timing, de-challenge or re-challenge, concomitant medication, concomitant diseases, and relevant history. Thus, the endpoint is not simply a count of every event; it concerns participants with events judged related to study medication.

The timeframe differs by component. For Midazolam, observation ran from the first midazolam dose on Day -1 until the first BI 474121 or placebo dose, up to 1 day. For the other groups, observation ran from the first BI 474121 or placebo dose until the last dose plus 7 days of residual effect period, up to 21 days. Results across these groups therefore refer to differently defined observation windows, which should be kept in mind when comparing percentages.

This endpoint is used in an early-phase study to describe tolerability and possible safety signals during the specified exposure and follow-up. It does not, by itself, establish the severity, duration, or clinical importance of each event. Nor does the percentage establish a causal effect: the drug-related classification relies on medical judgment, and the record does not provide event-level detail for this primary outcome. The observed percentages are best read as summaries for the defined groups and timeframes, rather than as a complete account of all potential safety outcomes.

7. Results Posted in the Registry

• Midazolam: 12.5% (5/40) versus 40.0% (4/10) on control; risk difference -27.5 percentage points (95% CI -59.5 to 4.5), risk ratio 0.31 (0.10–0.96); unadjusted two-proportion z-test p = 0.043.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary outcome summarized as a percentage: a participant either had at least one drug-related adverse event within the defined period or did not. The registry reports one percentage and one denominator for each group. This is a straightforward descriptive summary, but a percentage alone does not show how uncertain the underlying event frequency may be. With modest group sizes, a single participant’s classification can have a noticeable influence on the reported percentage.

What does a risk difference describe?

General statistical context: a risk difference subtracts the event proportion in one group from the event proportion in another, using the comparison’s stated ordering. A value below zero means the first proportion in that ordering is lower; a value above zero means it is higher. The posted Midazolam comparison reports a risk difference of -0.275 against Placebo (Part A). Its confidence interval extends across zero, indicating that the data are compatible with no difference as well as with possible differences in either direction. The interval is an expression of uncertainty around the estimate, not a range that guarantees the true value falls within it.

What does the p-value say?

General statistical context: a p-value describes how surprising data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions were true. 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 comparison reports an unadjusted p-value of 0.043. Because it is unadjusted and the record does not report how multiple outcomes or comparisons were handled, this value should be interpreted cautiously rather than as a stand-alone conclusion.

Why distinguish the study components?

The main dose evaluation is described as randomized, double-blind, placebo-controlled, and parallel group. The midazolam component is described separately as nested, open, fixed-sequence, and intra-individual. General statistical context: randomized parallel groups are intended to support comparison between assigned groups, while an intra-individual comparison uses measurements from the same participant under different conditions or times. An open component also differs from a masked component in how treatment knowledge is handled. These distinctions mean that a contrast involving the midazolam group should not automatically be interpreted as if it were a direct randomized comparison of two parallel arms. The registry does not give a detailed analysis plan for this contrast.

How should percentages across doses be read?

General statistical context: descriptive percentages can reveal how observed event frequencies vary, but they do not by themselves establish a trend, dose response, or causal relationship. The Part A percentages do not rise steadily at every successive listed dose, and the Part B groups have their own placebo comparator and different age group. Comparing across Part A and Part B therefore mixes age-part and dose differences. The registry record does not report adjusted estimates that account for these design features. Interpret the values within their named study groups and timeframes, rather than pooling or ranking them as if all were directly exchangeable.

What does the endpoint classification involve?

The endpoint is specifically the percentage of participants with drug-related adverse events, not the percentage with any adverse event. The record states that medical judgment considered the pattern and timing of a reaction, de-challenge or re-challenge, and relevant concomitant factors and history. General statistical context: outcome classification can affect an estimated percentage, particularly when judgments about attribution are involved. The record does not post enough event-level information to independently reassess those classifications or characterize the types and severity of primary-endpoint events.

What other statistical details are available?

The registry lists pharmacokinetic outcomes as secondary measures, including plasma exposure and maximum concentration measures for BI 474121 and midazolam. Those are different outcome types from a binary adverse-event percentage and require their own summaries and analysis methods. The registry record reports no analysis records for those secondary outcomes. It also does not report the trial’s formal statistical analysis plan, missing-data methods, interim analyses, or original sample-size justification. Consequently, the available summaries do not establish whether any adjustments, model-based analyses, or prespecified decision rules were used beyond what is explicitly stated in the record.

10. Confidence Intervals and Precision

Precision describes how much uncertainty surrounds an estimate. A point estimate such as a percentage or risk difference is a single summary of the observed data; a confidence interval expresses a range of values that remain compatible with the data under the method used. A narrower interval generally indicates greater precision, while a wider interval indicates greater uncertainty. A confidence interval is not a guarantee that the true value lies within its limits, and it does not by itself determine whether a difference is important.

The registry reports the arm-level primary endpoint percentages and group sizes but no confidence intervals for those individual percentages. Their precision is therefore not quantified in the posted arm summaries. The observed group sizes vary, including the Part B placebo group with 4.0 participants and the Midazolam group with 40.0. In general, estimates based on fewer observations tend to be less precise, though the amount of uncertainty also depends on the observed event frequency and the method used.

For the posted Midazolam versus Placebo (Part A) risk difference, the reported estimate is -0.275, and its confidence interval extends from a negative value to a positive value. Since zero lies within that interval, the data do not rule out no difference under the interval’s method. The interval also allows for differences in either direction. This uncertainty is consistent with caution in interpreting the unadjusted p-value of 0.043; neither summary should be treated as an isolated verdict.

Precision is also limited by the study’s structure. Part A and Part B concern different age groups, the doses are not identical across parts, and the observation period for Midazolam differs from the period used for the other groups. The midazolam component has a different design from the blinded parallel-group evaluation. The registry record does not report interval estimates for each dose group, adjusted comparison intervals, or an analysis plan explaining how uncertainty was to be assessed across all outcomes.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations are based on the observed Midazolam versus Placebo (Part A) effect, with scenarios for detecting 100% of that observed effect, 75% of the observed effect, and 50% of the observed effect. The values are participants per arm, not total participants or total events. The listed requirements are 39 and 52 participants per arm for 80% and 90% power when planning for 100% of the observed effect; 76 and 102 participants per arm when planning for 75% of the observed effect; and 183 and 245 participants per arm when planning for 50% of the observed effect.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The original design assumptions and sample-size justification for this trial are not reported in the registry record; these illustrations are based on a post hoc observed effect and should not be mistaken for the trial’s actual design target.

In plain terms, the 80% power column gives the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions. The 90% power column uses a higher chance of detection and therefore generally requires more participants per arm. Planning for a smaller effect requires more participants because smaller differences are harder to distinguish from random variation. These figures are planning illustrations, not observed power. Their assumptions do not show that the trial had adequate power for its primary endpoint or for other comparisons.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.400; treatment proportion p₁ = 0.125; average p̄ = 0.263.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6222 = 1.2196.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5911 = 0.4975.
4. n = (1.2196 + 0.4975)² / (-0.2750)² = 39.0, rounded up to 39 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.4                          # control proportion
p1 <- 0.125                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4537897)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 39 (80% power), 52 (90% power)
 75% of observed effect: n per arm = 76 (80% power), 102 (90% power)
 50% of observed effect: n per arm = 183 (80% power), 245 (90% power)
power.prop.test: 39 
Simulated power at n = 39 per arm: 0.816 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record identifies the primary endpoint and lists pharmacokinetic outcomes as secondary measures, but it does not report a statistical analysis plan explaining how the multiple outcomes or dose comparisons were handled. The posted Midazolam comparison has an unadjusted p-value of 0.043. Without a reported multiplicity strategy, it is unclear whether that p-value was intended as a confirmatory test, one of several exploratory comparisons, or subject to any planned adjustment. An unadjusted value should not be treated as if it accounts for all possible comparisons in the study.

Missing-data handling is not reported in the registry record. The record does not state how participants with incomplete follow-up, unavailable endpoint assessments, or missing pharmacokinetic measurements were treated. The arm-specific denominators are reported, but they do not by themselves explain whether any data were missing or why the denominators differ. No assumptions about missing outcomes or imputation should be inferred from these summaries.

The primary endpoint population is the treated set, defined in the record as randomized participants who received at least 1 dose of trial drug. The record does not report a separate intention-to-treat analysis, per-protocol population, or population-specific sensitivity analyses. Although enrollment is listed as 70, the endpoint group denominators vary. The relationship between overall enrollment, treatment exposure, and any participant exclusions from particular endpoint summaries is not further described in the registry record.

The record also does not report interim analyses, stopping rules, or the sponsor’s original sample-size justification. Those details could affect how the results were intended to be interpreted, but they cannot be reconstructed from the posted endpoint percentages. The reported values and the planning illustrations should therefore be kept distinct from unreported protocol or analysis decisions.

14. 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 serious adverse-event listing reports 0 affected participants in each listed group, and deaths are reported as 0 in each group. The at-risk denominators differ by group: 4 for Placebo (Part B), 8 for several BI 474121 groups, 10 for Placebo (Part A), and 40 for Midazolam. These are group-level safety summaries; the figures do not establish that every possible serious or delayed event was ruled out.

The registry also lists other adverse events separately from serious adverse events. Those counts should not be confused with the primary endpoint, which is the percentage of participants with drug-related adverse events and uses a stated attribution judgment and observation period. The record does not provide a list of serious-event terms, and no serious terms are listed. The absence of reported serious events in these groups is a description of the posted results, not evidence that risk is absent. Small group sizes and the limited observation windows constrain how much can be concluded about uncommon or later events.

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

The results describe drug-related adverse-event percentages observed among healthy participants receiving the listed treatments over the registry-defined timeframes. They show that the reported percentages vary among the BI 474121 and placebo groups, as well as in the Midazolam group. The comparison posted for Midazolam and Placebo (Part A) gives a risk difference of -0.275, with an unadjusted p-value of 0.043 and an interval that includes zero. The estimate and its uncertainty should be considered together, and the comparison’s distinct design context matters.

These results do not establish that BI 474121 is safe or unsafe, nor do they show that a particular dose is tolerated by all participants. A percentage summarizes whether participants had an event judged related to study medication; it does not describe the full clinical characteristics, severity, duration, or consequences of each event. The registry record does not provide the event-level detail needed to explore those features for the primary endpoint.

The study involved healthy participants in the specified young and elderly age ranges, with treatment over 14 days and follow-up windows up to 21 days for the non-midazolam groups. The results cannot establish what would occur with longer exposure, in people with health conditions, or in populations outside the stated age ranges. The different Part A and Part B groups also should not be collapsed into a single dose-response comparison: the age group, placebo group, and dose set differ across parts.

The record lists pharmacokinetic outcomes, but the results summarized in the registry do not include analyses for those measures. It also does not report the formal statistical plan, handling of missing data, or multiplicity approach. Consequently, the posted data support a bounded description of observed events and the one reported comparison, rather than broad conclusions about treatment effects or clinical use.

16. Why This Trial Matters Statistically

This study is statistically informative as an example of how early-phase safety summaries need to be read alongside design and precision. The primary result is a percentage of participants with drug-related adverse events, a useful descriptive measure for tolerability, but the reported group sizes are small and unequal. The percentages are therefore not equally precise, and a seemingly large difference in a small group can remain uncertain.

The trial also combines related but distinct questions. The randomized, double-blind, parallel-group component evaluated multiple BI 474121 doses against matching placebo in young and elderly groups. The midazolam interaction component had a nested, open, fixed-sequence, intra-individual design. Treating all arms as if they were interchangeable groups in one randomized comparison would overlook important design differences. Statistical interpretation depends not only on the numerical estimate but also on how the data were generated.

The Midazolam comparison illustrates why point estimates, intervals, and p-values need to be considered together. Its risk difference is -0.275 and its unadjusted p-value is 0.043, while its interval includes zero. The registry does not report how multiple comparisons were handled, so the p-value cannot be interpreted as a complete account of uncertainty across the study’s outcomes.

Finally, the record distinguishes the drug-related primary endpoint from serious and other adverse-event summaries, and it lists pharmacokinetic outcomes as secondary measures. Keeping those outcome types separate avoids overstating what any one summary can show. The record supports careful description, while leaving important analysis details unreported.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several features limit interpretation of the posted results. The study enrolled healthy participants in defined young and elderly age ranges, so the results do not directly describe other populations. The treatment period was 14 days, and the specified follow-up periods were limited; longer-term outcomes are not addressed by the reported primary endpoint timeframe.

Group sizes are small and differ across the listed arms. Some groups therefore provide limited information about uncommon events, and their percentages may be sensitive to individual participant classifications. The registry does not report confidence intervals for the individual arm percentages. It also does not provide enough primary-endpoint event-level detail to examine the nature or severity of events judged drug-related.

The study includes both a randomized, double-blind, parallel-group evaluation and a nested, open, fixed-sequence, intra-individual midazolam component. The components differ in design and endpoint observation period. The posted Midazolam versus Placebo (Part A) comparison should not be read as a straightforward randomized dose comparison, and its unadjusted p-value should be interpreted in light of the unreported multiplicity strategy.

The registry record does not report the formal statistical analysis plan, handling of missing data, interim analyses, or original sample-size justification. It lists pharmacokinetic outcomes, but no analysis records are posted for them. These gaps mean that some questions about prespecification, exclusions, and analysis choices cannot be resolved from the registry results alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study in Healthy Men and Women Who Are Either Between 18 - 45 Years or Between 65 - 80 Years to Test How Different Doses of BI 474121 Are Tolerated — NCT04537897.
• Registry record last updated 2024-03-08; status last verified 2023-07.
• Results first posted 2024-03-08.
• 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.

21. Record Summary

The registry record describes a completed phase 1, randomized, double-blind, parallel-group study of multiple rising oral doses of BI 474121 in healthy young and elderly male and female participants, with a nested midazolam interaction component in young participants. Enrollment is listed as 70. The primary endpoint is the percentage of participants with drug-related adverse events, with different observation periods for the Midazolam and other groups.

Reported primary endpoint percentages vary across the placebo and BI 474121 groups. The posted Midazolam versus Placebo (Part A) comparison has a risk difference of -0.275 and an unadjusted p-value of 0.043, while its confidence interval includes zero. Serious adverse-event counts and deaths are reported as 0 across the listed groups. The registry record does not report the formal analysis plan, missing-data methods, multiplicity approach, or original sample-size justification, so interpretation is descriptive and should account for the small, unequal groups and distinct study components.