A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain. (NCT03927209), a non-randomized phase 1 study. The primary outcome is Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging.

2. Clinical Question

3. Trial Design

This was a Phase I, open-label, non-randomized, parallel-group study in healthy male subjects. The registry record lists total enrollment as 10 and status as completed. The recorded start date was 2019-06-06 and primary completion date was 2019-11-22. Boehringer Ingelheim is listed as the sponsor.

The intervention was BI 1467335, administered orally in multiple doses. The primary endpoint description identifies a 10 mg group assessed on Day 28 and a 3 mg group assessed on Day 42. The brief study description likewise characterizes the high-dose period as 28 days and the low-dose period as 42 days. The record does not report further details of dose schedules or participant characteristics beyond the stated healthy male population.

Because allocation was non-randomized and the study had no masking, the dose groups should not be interpreted as randomized, blinded treatment arms. The primary endpoint was a baseline-to-treatment comparison within each group, rather than a comparison against a concurrent placebo or untreated group. Differences between dose groups could also reflect differences in the planned assessment day, as the endpoint time points differed by group. The registry record does not report a protocol rationale for those time points or a statistical plan for comparing the groups.

The primary endpoint population is called the PET set. Its description says it included subjects who were randomized and treated with at least one dose and had at least one baseline and one on-treatment PET scan. That wording refers to randomization even though the study allocation is listed as non-randomized. The number of participants meeting the PET-set criteria is not reported in the registry record. The detailed arm descriptions are also 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 subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Overall Study

Analysis population for the primary outcome, as defined in the registry: PET set (PETS): This set included all subjects who were randomized and treated with at least one dose of study drug for whom at least 1 PET scan at baseline and 1 on-treatment scan were provided.

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 randomized and treated with at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging, measured over Baseline (day -14 to -2) and last day of treatment (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group)..

The primary endpoint was percentage reduction in whole-brain monoamine oxidase B (MAO-B) availability assessed by positron emission tomography (PET) imaging. It compared the last treatment-day assessment with baseline: Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group. Baseline was defined as the period from day -14 to day -2. The endpoint was recorded as a percent reduction, with the mean and standard deviation specified as summary measures.

PET imaging was used to estimate MAO-B availability in the brain. The registry description says image analysis used PET emission data and a metabolite-corrected arterial plasma input function in an appropriate kinetic model to generate an outcome parameter proportional to target availability at each PET scan. In general, a baseline comparison can describe how a measured quantity changes within participants over time. A PET-based measure is a biomarker measurement; its interpretation depends on the imaging and analysis methods as well as the population assessed.

The registry record does not report the mean percentage reduction, its standard deviation, or the number of participants contributing to the primary endpoint. Therefore, the magnitude and precision of the primary endpoint cannot be characterized from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the mean describe?

The primary endpoint is a continuous measure expressed as percent reduction in whole-brain MAO-B availability. The registry specifies the mean as its summary measure. In general, a mean describes the average value across the participants included in an analysis. It can provide a compact description of a group, but it does not show how individual measurements are distributed. The standard deviation is listed as the measure of dispersion; in general, it describes the spread of individual observations around the mean. Neither the mean nor the standard deviation for the primary endpoint is reported in the registry record.

What does the PET measurement involve?

The record describes PET imaging with the [11C]-L-deprenyl-D2 tracer as the method for assessing brain MAO-B occupancy or availability. For the primary endpoint, image analysis generated an outcome parameter proportional to target availability at each PET scan. The analysis used PET emission data and a metabolite-corrected arterial plasma input function in an appropriate kinetic model. In general, kinetic models combine measurements over time with information about tracer availability to estimate a biological quantity of interest. A model-based estimate is not a direct count of enzyme molecules; it depends on the measurement process and the assumptions of the model. The particular model specification and diagnostic checks are not reported in the registry record.

What does a baseline comparison tell the reader?

The endpoint compared the on-treatment assessment with baseline for each dose group. Baseline was specified as day -14 to day -2, and the last treatment-day assessment was Day 28 for the 10 mg group and Day 42 for the 3 mg group. In general, measuring participants at baseline and again during treatment can describe within-participant change. Pairing measurements can account for some stable differences between participants, but it does not create a randomized control group. The record does not state the exact statistical method used to calculate the reported percentage reduction or to account for paired observations.

How should uncertainty be understood?

In general, a confidence interval expresses the range of values compatible with the data and the statistical method, while reflecting sampling uncertainty. A narrow interval indicates greater precision than a wide interval, but neither width nor statistical significance alone establishes clinical importance. The registry record does not report a confidence interval or other uncertainty interval for the primary endpoint. It also does not report a primary endpoint p-value or a detailed analysis procedure. The absence of these values means the precision of the observed change cannot be assessed from this record.

Why can dispersion matter?

In general, substantial variability among participants makes a group mean less representative of any one participant and can reduce precision. Some continuous measurements may also have variability that is not well described by a simple normal distribution. Over-dispersion refers generally to variability greater than a statistical model expects; if present, it can make model-based uncertainty estimates too small unless the analysis accommodates it. The registry record does not report whether over-dispersion was assessed or whether any alternative variance method was used. No conclusion about its presence can be made from the listed endpoint description.

What can planning calculations establish?

Any sample-size calculations associated with these results are planning illustrations based on the observed effect, not evidence of observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. In general, such calculations show the participant count that would be needed under those assumptions to detect a specified effect. They do not describe the study's original design justification and do not establish that the trial had a particular probability of detecting an effect. The registry record does not report a sample-size justification from the trial protocol. The observed primary effect and resulting planning counts are not reported in the registry record, so no numerical planning interpretation is possible from the available information.

The record lists zero analyses. This does not supply a detailed account of every statistical procedure performed; the analysis methods and any deviations from a protocol are not reported in the registry record. Statistical interpretation should therefore distinguish the stated endpoint definition from results and methods that are not documented.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("BI 1467335 10 Milligram (mg)", "BI 1467335 3 Milligram (mg)")
n   <- c(5, 4)
m   <- c(72.58, 2.43)
sp  <- c(11.81, 6.05)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  BI 1467335 10 Milligram (mg)  5  72.580  11.810  57.916  87.244
CARM  BI 1467335 3 Milligram (mg)  4  2.430  6.050  -7.197  12.057

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary endpoint and five secondary outcome descriptions, for six outcome measures overall. Secondary outcomes include MAO-B availability at additional time points, platelet-rich plasma MAO-B inhibition, maximum measured plasma concentration, and area under the concentration-time curve from 0 to 24 h. Listing multiple outcomes creates the general possibility of multiplicity: when several outcomes or comparisons are examined, the chance of at least one apparently noteworthy result can increase. The record does not report a multiplicity adjustment or a strategy for prioritizing secondary analyses, so such a plan is not reported in the registry record.

Results for the primary and secondary outcomes are not reported in the registry record. The record lists zero analyses, and does not provide analysis-level estimates or participant counts for the endpoint outcomes. It therefore does not support assessment of which participants contributed to each outcome or whether all planned outcomes were analyzed.

The primary endpoint population is described as the PET set, defined using treatment and baseline and on-treatment scan criteria. The description includes the term randomized despite the study's non-randomized allocation. The number meeting the PET-set criteria is not reported in the registry record. The record also does not report how missing scans, incomplete endpoint measurements, or other missing outcome data were handled. It does not state whether any imputation, exclusion, or sensitivity analysis was used. These details matter because the analyzed participants and the handling of missing measurements can affect both the estimate and its precision.

No statistical analysis plan, interim analysis plan, or missing-data procedure is reported in the registry record. Their absence from the record should not be interpreted as evidence that a particular procedure was or was not used; it means the procedure cannot be described from the information available.

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 lists serious adverse event counts for the two dose groups and the total on-treatment group. In the BI 1467335 10 mg group, 0 serious adverse events were listed among 5 participants at risk. In the BI 1467335 3 mg group, 0 serious adverse events were listed among 5 participants at risk. The total on-treatment group had 0 serious adverse events among 10 participants at risk. Deaths were listed as 0 in each group and in total. No serious adverse event terms are listed.

For other adverse events, the record lists 5 affected participants among 5 at risk in the 10 mg group, 3 among 5 at risk in the 3 mg group, and 8 among 10 at risk overall. These are participant counts, not counts of distinct event types or measures of severity. The categories should not be conflated: the serious-event counts are separate from the other adverse event counts listed in the record.

In general, zero recorded serious events in a small study does not establish that a serious event cannot occur, and group counts alone do not describe the nature, timing, or duration of events. The registry record does not provide serious-event terms or further event-level detail. These figures describe the posted counts and should not be interpreted as a comparison establishing a safety difference between doses.

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

The study was designed to examine whether multiple oral doses of BI 1467335 were associated with a change in brain MAO-B availability relative to baseline in healthy male subjects. It used PET imaging and specified a mean percentage reduction as the primary endpoint. The assessment was scheduled for Day 28 in the 10 mg group and Day 42 in the 3 mg group. These details define the measurement question, not the result.

The registry record does not report primary endpoint estimates. It therefore cannot establish the size or direction of the measured change, its variability, or its statistical precision. The secondary outcome descriptions also do not provide numerical findings. No conclusion about the amount of MAO-B change can be drawn from the endpoint name or the planned analysis time points alone.

Even if a within-group change were reported, a baseline comparison in a non-randomized, open-label study would describe change among those measured rather than isolate the effect of treatment against a randomized control. The dose groups were assessed at different treatment durations, so a direct group contrast would not separate dose from time without an appropriate design and analysis. The registry record does not report such a comparison.

The results described do not address effects in populations other than the healthy male participants enrolled. The record also does not provide clinical outcomes that would establish how a PET measure relates to symptoms or other outcomes. MAO-B availability is the biological measurement specified as the endpoint; the record does not report findings that allow an inference about clinical benefit or harm.

The adverse event counts show that no serious adverse events or deaths were recorded in the listed groups, alongside other adverse events in the counts reported. Those observations are limited to the study participants and the information in the registry record. They cannot establish the absence of risk. The record's main interpretive limit is that it describes the study question and procedures but does not report the outcome estimates needed to quantify the measured effect or its uncertainty.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of a biomarker study whose design and endpoint are described more fully than its results. The record identifies a PET-based measure of whole-brain MAO-B availability, baseline and treatment assessment periods, and a mean with standard deviation as the intended summary. Those details help define what an outcome estimate would represent. Without the estimate and its dispersion, however, readers cannot judge the magnitude or precision of the measured change.

The non-randomized, open-label, parallel-group design also shapes the comparisons that can be supported. The primary endpoint was framed as a change from baseline within each dose group, not a randomized comparison against a control group. In general, this distinction is important: a within-group measurement can document change over time, while attribution of that change to an intervention calls for stronger control of competing explanations. The registry record does not describe methods that would provide a randomized causal contrast.

Different endpoint days for the 10 mg and 3 mg groups add another interpretive consideration. If the groups were compared, dose and duration would differ together. This makes clear why a dose-group contrast cannot be treated as a simple like-for-like comparison based on the design information alone.

The endpoint population definition and the non-randomized allocation wording are not fully aligned: the PET-set description refers to randomized participants. The number included in the PET set is not reported. Transparent reporting of the analysis population and missing-data handling is important because estimates depend on which participants contribute measurements. Here those details, as well as the numerical outcome findings, are not reported in the registry record.

Finally, the listed safety counts illustrate the distinction between recorded events and broader conclusions. Counts from a small study can describe what was recorded among participants, but cannot establish the absence of events or a comparative safety profile. These statistical features make the record useful for understanding the planned measurement, while also defining clear limits on inference.

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 does not report numerical results for the primary endpoint or secondary outcomes. Consequently, the observed mean percentage reduction, standard deviation, confidence interval, and p-value cannot be described. The total enrollment is 10, but the number contributing to the PET endpoint is not reported in the registry record, so total enrollment cannot be assumed to equal the analyzed population.

Allocation was non-randomized and masking was absent. There was no randomized control group identified for the primary baseline comparison. The design therefore does not support treating dose groups as equivalent control arms. The 10 mg and 3 mg groups also had different primary assessment days, Day 28 and Day 42, respectively, which complicates any direct comparison between groups.

The PET-set description refers to participants who were randomized, although the allocation is listed as non-randomized. The record does not clarify this wording or report the number meeting the PET criteria. It also does not describe missing-scan handling, exclusions, imputation, or sensitivity analyses. Detailed dose schedules and arm descriptions are not reported in the registry record.

The registry record does not report a statistical analysis plan, multiplicity strategy, sample-size justification, interim analyses, or the detailed model specification used for endpoint analysis. The stated PET method describes use of an appropriate kinetic model but does not identify its specifications or diagnostics. These omissions limit assessment of how the planned analysis was carried out and how robust any estimate would be. Since numerical endpoint findings are absent, those uncertainties cannot be weighed against observed results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain. — NCT03927209.
• Registry record last updated 2021-06-22; status last verified 2021-06.
• Results first posted 2021-06-04.
• 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

This completed Phase I study enrolled 10 healthy male subjects and evaluated multiple oral doses of BI 1467335 in a non-randomized, open-label, parallel-group design. The primary endpoint was percentage reduction in whole-brain MAO-B availability assessed by PET imaging relative to baseline. The last treatment-day assessment was Day 28 for the 10 mg group and Day 42 for the 3 mg group.

The registry record lists six outcome measures, including the primary PET endpoint and secondary imaging, platelet-rich plasma, and plasma pharmacokinetic measures. It describes the PET set and specifies the mean and standard deviation for the primary endpoint. The record lists 0 serious adverse events in both dose groups and 0 deaths; other adverse events affected 5 participants in the 10 mg group and 3 in the 3 mg group.

Numerical primary and secondary outcome results, endpoint analysis counts, and details of missing-data handling are not reported in the registry record. As a result, the magnitude and precision of the primary measured change cannot be assessed from the record.