Safety, Tolerability, and Pharmacokinetics of Single Doses BI 425809: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, and Pharmacokinetics of Single Doses BI 425809 (NCT02068690), a randomized phase 1 study. The primary outcome is Number of Participants With Drug-related Adverse Events (AE).

2. Clinical Question

This was a Phase 1 study in healthy participants, not a trial of clinical benefit in people with a disease. Its stated aims were to investigate safety, tolerability and pharmacokinetics after single rising oral doses; explore dose proportionality for the oral solution; and investigate relative bioavailability under different formulation and food conditions. The registry lists pharmacokinetic outcomes as secondary outcomes, including maximum plasma concentration and area under the concentration-time curve.

The posted primary outcome is a count of participants with drug-related adverse events, rather than a count of all events or a measure of symptom severity. The study therefore addresses whether such events were reported in the different study groups, not whether treatment improves a health outcome. The posted counts can describe what happened among these participants, but their small group sizes make comparisons imprecise.

3. Trial Design

The registry describes a randomized Phase 1 study with an overall enrollment of 83 and a crossover model. Its title describes two parts with different designs. The single rising dose part is described as partially randomized, single-blind and placebo-controlled; the bioavailability and food-effect part is described as open-label, randomized and three-way crossover. The registry’s top-level masking classification is none. These descriptions indicate that masking differed by part, rather than applying one uniform masking approach to the entire study.

In the single rising dose part, participants received a single oral dose of placebo or one of the listed BI 425809 oral-solution doses: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg or 150 mg. The registry lists 18 participants in the placebo group and 6 in each active-dose group. The primary outcome timeframe for this part ran from first drug administration to the end of study, up to 18 days.

In the bioavailability and food-effect part, participants received 25 mg BI 425809 as a tablet without food, a tablet after a standardized high-fat, high-calorie meal, and an oral solution without food. The registry lists six possible treatment sequences, each with 11 participants. This crossover arrangement means a participant received the three treatments in a sequence; it is distinct from a parallel-group comparison in which each participant receives only one regimen. The outcome timeframe for this part was from first administration through the end of the intervention period, up to 18 days for each intervention.

The registry lists the study as completed, with start on 2014-03-20 and primary completion on 2014-09-10. Further protocol details, including the rationale for the group sizes, are not reported in the registry record.

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 group if any of the entry criteria were violated.

Only the first 6 of 16 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Treated set (TS) - All participants who were treated with at least 1 dose of the study medication.

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) - All participants who were treated with at least 1 dose of the study medication.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Drug-related Adverse Events (AE), measured over SRD Part: From the time of first drug administration until the end of study, up to 18 days. BA/FE Part: From the time of first drug administration until the end of the intervention period, up to 18 days for each intervention..

The primary endpoint counts participants with at least one adverse event judged by the investigator to be related to study drug. It is a participant-level count: the endpoint does not give the total number of events, their duration, or their severity. Drug-relatedness is an investigator assessment, so this outcome reflects both the occurrence of an adverse event and the investigator’s judgment about its relationship to study medication.

The registry defines the analysis population as the treated set: participants who received at least one dose of study medication. The timeframe covered the period from first drug administration to the end of study in the single rising dose part, up to 18 days, and from first administration to the end of the intervention period in the bioavailability and food-effect part, up to 18 days for each intervention.

This kind of endpoint is used in an early-phase study to describe tolerability and monitor possible drug-related events after exposure. Reporting the number of participants affected makes the group-level experience easy to interpret, but it does not reveal the number of events per affected participant. Nor does a count alone establish that a drug caused an event: the registry says that the investigator assessed relatedness, and the endpoint records that assessment.

The primary outcome should also be distinguished from the separate serious adverse event outcome. In the posted results, no participants are listed as affected by a serious adverse event in any group. The primary endpoint includes investigator-assessed drug-related adverse events generally and is not limited to serious events.

7. Results Posted in the Registry

• BA/FE Part: Tablet Without Food: 27.3% (3/11) versus 16.7% (3/18) on control; risk difference 10.6 percentage points (95% CI -20.8 to 42.1), risk ratio 1.64 (0.40–6.73); unadjusted two-proportion z-test p = 0.494.
• BA/FE Part: Tablet With Food: 9.1% (1/11) versus 16.7% (3/18) on control; risk difference -7.6 percentage points (95% CI -31.8 to 16.6), risk ratio 0.55 (0.06–4.61); unadjusted two-proportion z-test p = 0.566.
• BA/FE Part: Oral Solution Without Food: 36.4% (4/11) versus 16.7% (3/18) on control; risk difference 19.7 percentage points (95% CI -13.5 to 52.9), risk ratio 2.18 (0.60–7.97); unadjusted two-proportion z-test p = 0.229.

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help put the posted counts and recalculated comparisons in context. The primary outcome is binary at the participant level: a participant either was or was not recorded as having a drug-related adverse event during the relevant period. The reported count is the number affected, accompanied by the group size. This preserves the distinction between the number of people affected and the number of events experienced.

What does a risk difference describe?

In general, a risk difference subtracts the event proportion in one group from the event proportion in another group. A value above zero means the event proportion is higher in the first group as defined by the comparison; a value below zero means it is lower. A value of zero represents no difference in the observed proportions. The reported recalculations express this contrast on an absolute scale, which can be more directly interpreted as a difference in event frequency than a relative measure. No new risk differences are calculated in this discussion.

How should a confidence interval be read?

In general, a confidence interval gives a range of values compatible with the data and the method used to estimate the effect. It is not a guarantee that the true value lies in the interval, nor is it a range containing a fixed proportion of individual outcomes. A wide interval means the estimate is imprecise. For the three recalculated comparisons, each interval includes zero and also extends to values on both sides of zero. This signals that the observed group counts do not pin down the direction or size of a difference with precision.

What does a p-value convey?

In general, a p-value measures how unusual data at least as extreme as those observed would be under a specified no-difference model and the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. The unadjusted p-values posted for the recalculated comparisons are 0.494, 0.566 and 0.229. Considered alongside the confidence intervals and the small groups, these values do not provide a precise distinction between the compared groups. They should not be read as evidence that treatments are equivalent.

Why does the crossover structure matter?

In general, crossover studies compare treatments received by the same participant, which can help account for stable differences between participants. A suitable analysis usually needs to respect the paired treatment structure and the sequence in which treatments were given. The bioavailability and food-effect part used three treatment sequences, but the recalculated adverse-event comparisons are unadjusted comparisons against the separate placebo group. They do not use the within-participant structure as a crossover analysis would. The registry record does not report the statistical model or other details for the sponsor’s analysis of the primary endpoint, so those methods cannot be inferred from the design description alone.

Why are the dose-group counts uncertain?

In general, estimates from small groups vary considerably with the outcome of even one participant. The single rising dose groups each contain 6 participants, while the placebo group contains 18. As a result, the observed counts are useful descriptions of these participants but are limited for estimating event rates in a broader population. A count such as 6 of 6 at 150 mg is an observed group result; it does not establish what would occur in a larger group or identify the cause of each event.

What can be concluded from the posted methods information?

The registry identifies the primary outcome, its timeframe and the treated-set population. It also lists secondary pharmacokinetic outcomes: maximum plasma concentration and area under the concentration-time curve for the single rising dose and bioavailability and food-effect parts. However, the statistical analysis plan, adjustment methods, handling of missing outcomes and justification for the original sample size are not reported in the registry record. The recalculated comparisons are explicitly unadjusted and should not be mistaken for a complete account of the original analysis plan.

General statistical interpretation also depends on the question being asked. A safety description can identify counts and patterns that merit attention, while a test of a difference asks whether the observed data are sufficiently informative under a particular model. These are related but distinct tasks. In this trial, the primary counts provide a descriptive account; the recalculated comparisons add estimates and uncertainty for three contrasts, but do not replace a detailed sponsor analysis or broader evidence.

10. Confidence Intervals and Precision

The risk-difference confidence intervals are broad relative to the estimates. For tablet without food compared with placebo, the estimate is 0.106 and the 95% confidence interval runs from -0.208 to 0.421. For tablet with food, the estimate is -0.076 and the interval runs from -0.318 to 0.166. For oral solution without food, the estimate is 0.197 and the interval runs from -0.135 to 0.529. All three intervals include zero, and each also includes values on both sides of zero.

In general, this pattern means the data are not precise enough to identify a single direction and magnitude for the group difference. The estimates are based on 18 participants in the placebo group and 11 participants in each bioavailability and food-effect treatment group. With small denominators and few events, a change in the outcome of one participant can materially alter a group count and its estimated contrast.

The risk-ratio and odds-ratio estimates also have wide confidence intervals. For tablet without food, the risk ratio was 1.636, with interval 0.398 to 6.727; the odds ratio was 1.875, with interval 0.305 to 11.52. For tablet with food, the risk ratio was 0.545, with interval 0.065 to 4.614; the odds ratio was 0.5, with interval 0.045 to 5.514. For oral solution without food, the risk ratio was 2.182, with interval 0.597 to 7.969; the odds ratio was 2.857, with interval 0.499 to 16.36. These intervals likewise allow a broad range of relative effects.

Confidence intervals describe sampling uncertainty under their calculation method; they do not account for every limitation, such as unreported analytic choices or differences between study parts. They are not evidence of equivalence. The registry does not report a prespecified equivalence margin or a non-inferiority margin for these comparisons.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design. They are participants per arm for 80% power and participants per arm for 90% power; they are not total events. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For each illustration, the effect to detect is the stated fraction of the observed effect.

For the comparison of tablet without food with placebo, the figures for planning for 100% of the observed effect are 239 participants per arm for 80% power and 319 for 90% power. Planning for 75% of the observed effect gives 406 and 543 participants per arm, respectively; planning for 50% gives 869 and 1,163. For tablet with food, the corresponding pairs are 306 and 409, 579 and 774, and 1,377 and 1,842. For oral solution without food, they are 78 and 104, 131 and 174, and 273 and 365.

In general, the 80% column gives the per-arm size estimated to provide an 80% chance of detecting the specified effect under the planning assumptions if that effect is real. The 90% column uses a higher target chance and therefore gives larger figures. Across each comparison, planning for a smaller fraction of the observed effect requires more participants. These figures are not observed power; they are prospective illustrations based on effects observed in small groups, not the trial’s original sample-size justification. The registry does not report the original design assumptions.

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 = 0.167; treatment proportion p₁ = 0.273; average p̄ = 0.220.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5855 = 1.1476.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5807 = 0.4887.
4. n = (1.1476 + 0.4887)² / (0.1061)² = 238.0, rounded up to 239 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 <- 0.166666666666667                          # control proportion
p1 <- 0.272727272727273                          # 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(2068690)
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 = 239 (80% power), 319 (90% power)
 75% of observed effect: n per arm = 406 (80% power), 543 (90% power)
 50% of observed effect: n per arm = 869 (80% power), 1,163 (90% power)
power.prop.test: 238 
Simulated power at n = 239 per arm: 0.803 (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 lists 5 outcome measures and 6 analyses, including the primary count outcome and secondary pharmacokinetic outcomes. The secondary outcomes cover maximum plasma concentration and area under the concentration-time curve in the single rising dose and bioavailability and food-effect parts. The presence of multiple outcomes and analyses raises the general issue of multiplicity: when many hypotheses are tested, the chance of at least one apparently notable result can increase. Whether and how that issue was addressed is not reported in the registry record.

The three risk-difference comparisons discussed in the statistical interpretation are unadjusted recalculations. Their p-values are therefore not adjusted for multiple comparisons. The registry record does not report a multiplicity adjustment or a hierarchy of confirmatory tests for these comparisons. As a result, they should be treated as descriptive exploratory contrasts rather than a family of confirmatory tests with a reported overall error-control strategy.

The treated set is defined as all participants who received at least one dose of study medication. The registry does not report how missing endpoint observations were handled, whether any participants had missing primary outcome data, or whether additional analysis populations were used. It also does not report the statistical model used for the original primary analysis or how the crossover structure entered the bioavailability and food-effect analysis.

These omissions do not change the posted counts, but they limit assessment of the complete analysis process. In particular, the group counts alone cannot show whether any observations were excluded or how protocol deviations were handled. Those details are not reported in the registry record.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list 0 affected participants in every group. That includes the placebo group, all single rising dose groups from 0.5 mg through 150 mg, and the tablet-without-food, tablet-with-food and oral-solution-without-food groups. The reported numbers at risk are 18 for placebo, 6 for each single-dose group and 11 for each bioavailability and food-effect treatment group.

These are counts of participants recorded as having a serious adverse event, not counts of all adverse events. They should be read separately from the primary endpoint, which counts participants with an adverse event judged by the investigator to be drug-related. The posted primary counts include affected participants in each part, while the serious adverse event counts are zero throughout.

A zero count in these small groups describes the observations in this study; it does not establish that serious adverse events cannot occur or that a larger study would also observe none. Death values are not reported in the registry record. The registry’s serious-event listing does not name any serious-event terms.

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

The posted results describe the number of participants who experienced investigator-assessed drug-related adverse events during the stated study periods. In the single rising dose part, the counts ranged from 1 to 6 among groups of 6 at active dose levels, while 3 of 18 participants in the placebo group were affected. In the bioavailability and food-effect part, the counts were 3 of 11 for tablet without food, 1 of 11 for tablet with food and 4 of 11 for oral solution without food. No participants were listed as having a serious adverse event in any group.

The three unadjusted recalculated risk differences have confidence intervals that include zero and extend to differences in either direction. The data therefore do not precisely establish the direction or magnitude of differences between these treatment groups and placebo. They also do not establish equivalence, because the registry does not report an equivalence margin and the estimates are imprecise.

These findings are limited to the participants and observation periods recorded for this Phase 1 study in healthy male volunteers. They do not directly answer questions about longer treatment, different populations, or clinical benefit. The study’s stated aims include pharmacokinetic investigation, but numerical pharmacokinetic results are not included in the registry record discussed in this interpretation.

Most importantly, the counts should not be translated into a claim that a treatment works or does not work, or into a prediction for an individual. They are descriptive safety observations from small groups. The study can characterize what was recorded after these single-dose and crossover exposures, but the posted event counts and recalculated comparisons cannot establish broad safety conclusions.

16. Why This Trial Matters Statistically

Statistically, this study illustrates the distinction between describing observed events and estimating differences with precision. The primary endpoint is a participant count, which is straightforward to understand, but the active-dose groups contain 6 participants each and the crossover treatment groups contain 11 each. Counts in groups this small provide limited precision and can change substantially when the outcome for a single participant differs.

The trial also combines two different design questions. The single rising dose part examines adverse events across placebo and increasing oral-solution dose groups. The bioavailability and food-effect part compares three 25 mg regimens in a randomized crossover design. Treating these parts as if they were one uniform parallel-group comparison would ignore their different structures and purposes.

The unadjusted recalculations demonstrate why estimates should be interpreted with their confidence intervals rather than p-values alone. The estimates have uncertainty in both directions, and the intervals are broad. This is more informative than treating a p-value as a simple pass-or-fail result, but it still does not resolve the underlying uncertainty.

For clinical researchers, the record also highlights the value of complete reporting. Details about the original sample-size rationale, missing data, analysis model and multiplicity strategy are not reported in the registry record. Without those details, readers can describe the posted observations and assess the displayed recalculations, but cannot fully reconstruct the planned inferential analysis.

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.

The primary limitation for interpreting event frequencies is the small group size. The single rising dose arms each have 6 participants, and each treatment group in the bioavailability and food-effect part has 11. These counts support description of the enrolled participants but provide limited precision for estimating event rates beyond them.

The study enrolled healthy male volunteers and involved single-dose administration. The registry record therefore does not establish how the observations would apply to other populations or longer exposure. This limitation follows from the population and design described in the record, not from an assumption about the participants’ clinical risks.

The overall trial contains two distinct parts: a partially randomized, single-blind, placebo-controlled single rising dose part and an open-label, randomized three-way crossover part. The recalculated contrasts compare the crossover treatment groups with the placebo group, rather than using a reported within-participant crossover analysis. The registry does not report the sponsor’s statistical model for the primary endpoint, so the recalculations should not be treated as a reconstruction of that model.

The registry does not report the original sample-size justification, missing-data methods, handling of protocol deviations, multiplicity strategy or detailed analysis populations beyond the treated-set definition for the primary outcome. Numerical results for the listed pharmacokinetic secondary outcomes are not included among the registry entries. The registry record also does not report deaths. These reporting gaps limit a fuller assessment of the intended analysis and the breadth of conclusions that can be drawn.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety, Tolerability, and Pharmacokinetics of Single Doses BI 425809 — NCT02068690.
• Registry record last updated 2026-06-03; status last verified 2026-05.
• Results first posted 2026-05-05.
• 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

NCT02068690 is a completed Phase 1 study sponsored by Boehringer Ingelheim. It enrolled 83 healthy participants and examined single rising oral-solution doses of BI 425809, as well as relative bioavailability and food effect for 25 mg tablet and oral-solution regimens. The registry describes the dose-escalation part as partially randomized, single-blind and placebo-controlled, and the formulation part as open-label, randomized and three-way crossover.

The primary outcome was the number of treated-set participants with an adverse event judged by the investigator to be related to study drug. The posted counts are small, and the unadjusted recalculated risk differences have broad confidence intervals that include zero. No participants were listed as having a serious adverse event. These observations describe the study groups but do not provide precise estimates of comparative risk or establish equivalence.