A Study to Test How Well Different Doses of BI 754132 Are Tolerated in Patients With an Advanced Form of Age-related Macular Degeneration Called Geographic Atrophy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Test How Well Different Doses of BI 754132 Are Tolerated in Patients With an Advanced Form of Age-related Macular Degeneration Called Geographic Atrophy (NCT04002310), a non-randomized phase 1 study. The primary outcome is SRD Part: Number of Patients With Ocular (in the Study Eye) or Systemic Dose Limiting Events (DLEs).

2. Clinical Question

This was an early-phase safety and tolerability study, not a controlled test of clinical benefit. Its stated purpose was to assess tolerability across different doses of BI 754132. The registry also describes regular checks of participants’ general health and lists pharmacokinetic outcomes, including serum concentration measures after single or repeated dosing.

The primary endpoint combines events from two domains: ocular events in the study eye and specified systemic events. That makes it a safety measure rather than a measure of change in geographic atrophy or vision. The registry’s definition of systemic dose-limiting events includes drug-related adverse events of moderate or severe intensity, as defined by the investigator, and names several symptoms and event types. The observed number of participants meeting the endpoint is not reported in the registry record, so the primary question cannot be answered from the posted results.

3. Trial Design

This phase 1 study enrolled 18 participants and is recorded as terminated. It was open label, non-randomized and uncontrolled, with a sequential model. Participants and study doctors were not masked to treatment assignment according to the registry’s masking classification. The record does not report a parallel control group.

The study had a single rising dose part and a multiple dose part. In the single rising dose part, BI 754132 was administered as one intravitreal injection at dose levels of 0.3 mg, 1 mg, 3 mg or 6 mg. The registry descriptions indicate that escalation proceeded sequentially, with safety assessments after an initial participant at a dose before further dosing at that level. The available description is truncated for some dose groups, so additional operational details are not reported in the registry record. In the multiple dose part, participants received 6 mg as three intravitreal injections separated by 4 weeks.

The study drug was described as being given to humans for the first time. The brief description says participants were in the study for about 4 months and visited the site about 10 times. The primary endpoint applied only to participants in the single rising dose part, rather than to everyone enrolled across both parts. The registry defines its treated set as all participants who received at least one dose, restricted to those included in the single rising dose part.

Because dose assignment was non-randomized and the study had no control group, differences among dose groups are descriptive. The groups cannot be treated as exchangeable comparison arms: dose level and sequential enrollment are intertwined, and no randomized allocation is described. The registry record does not report a protocol-based sample-size justification, a prespecified statistical analysis plan, interim analyses, or a rationale for terminating the study. Those design details should not be inferred from the enrollment or the posted safety counts.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated Set (TS): The TS consisted of all patients who were treated with at least 1 dose of BI 754132. Only participants included in the SRD part.

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 consisted of all patients who were treated with at least 1 dose of BI 754132.

6. Primary Endpoint

The registry lists the primary outcome as SRD Part: Number of Patients With Ocular (in the Study Eye) or Systemic Dose Limiting Events (DLEs), measured over From drug administration until end of trial, up to 100 days..

The primary endpoint counts participants in the single rising dose part who experienced an ocular dose-limiting event in the study eye or a systemic dose-limiting event after drug administration. The specified observation period runs from administration until the end of the trial, up to 100 days. The endpoint is a participant count, not a measure of event severity averaged across the group or a time-to-event estimate.

The registry defines systemic dose-limiting events as drug-related adverse events, as judged by the investigator, of moderate or severe intensity on the Common Terminology Criteria for Adverse Events scale. The stated examples include diarrhea, cough, and participant-reported paraesthesia, dysgeusia, taste abnormality, taste disorder or hyposmia. Ocular events are limited by the endpoint description to the study eye. The endpoint description does not provide a separate event threshold for the ocular component beyond identifying it as a dose-limiting event.

A dose-limiting-event count is used in early-phase research to describe whether participants experience specified safety events while receiving a dose. It can inform tolerability assessment across sequential dose levels, but a count alone does not establish that a dose caused an event. Nor does it quantify efficacy. The observed primary endpoint count is not reported in the registry record. Consequently, the endpoint’s definition and follow-up window are available, but the primary safety result itself cannot be interpreted from the recorded information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information is limited. The registry identifies a participant-count endpoint and describes a treated set for the primary outcome, but it lists zero analyses. It does not report an analysis model, an estimate for the primary endpoint, a confidence interval, or a p-value. The following concepts explain how such information is generally interpreted; they are not claims about additional analyses performed in this study.

What does a participant count represent?

A count records how many participants satisfy an endpoint definition during the stated observation period. For this primary outcome, the endpoint is whether a treated participant in the single rising dose part experienced at least one qualifying ocular or systemic dose-limiting event. A participant count differs from an event count: one participant could potentially have more than one event, while a participant-level endpoint generally classifies whether the participant met the definition. The registry’s primary outcome is explicitly expressed as a number of participants.

Counts are most informative when their population, event definition and observation window are clear. Here, the population is restricted to the treated set in the single rising dose part, and the follow-up period is from administration until the end of the trial, up to 100 days. The primary count itself is not reported in the registry record. The separate adverse-event counts should not be substituted for it because their definitions and reporting categories are not identical to the primary endpoint.

Why does the design matter for dose comparisons?

Random allocation is one way to reduce systematic differences between groups in a comparative study. This study was non-randomized, sequential and uncontrolled. As a result, the dose groups are descriptive cohorts, not randomized arms. A difference in counts between two dose groups could reflect dose, the sequence in which participants entered, or other differences that the registry does not characterize. Statistical adjustment can sometimes address measured differences, but an adjusted analysis is not reported in the registry record, and adjustment would not turn a non-randomized study into a randomized one.

The single rising dose part and the multiple dose part also answer different descriptive questions. The former used one injection at several dose levels; the latter used repeated 6 mg dosing. Comparing those parts directly would mix dose schedule with study part and would not be a like-for-like contrast. The registry cautions that the groups are not a control comparison.

What would uncertainty measures add?

A confidence interval is a range calculated from data and a statistical method to express uncertainty around an estimate. For a participant-count endpoint, an interval around a proportion or another clearly defined estimate can show how imprecisely the result is known. Small groups generally produce less precise estimates than larger groups, and a count alone does not show that uncertainty. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from an interval.

A p-value, when used, measures how incompatible data are with a specified null model under its assumptions. It does not measure the probability that a treatment works, nor does it establish causality. No p-value or primary endpoint analysis is reported. Given the absence of a randomized comparator, a p-value from a between-group comparison would not by itself overcome confounding or the sequential structure.

How should the sample-size illustrations be understood?

Planning illustrations are distinct from observed trial results and from a study’s original design calculation. The described illustrations use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. For time-to-event settings, the stated approach gives a total event count; other settings give participants per arm. These assumptions describe an illustrative calculation, not a design feature of this study. The registry record does not report that the trial was designed using those assumptions, and the illustrations must not be called observed power. In addition, a non-randomized, uncontrolled dose-escalation study does not have the two comparable randomized arms assumed by that planning setup.

Why can event variability matter?

For count outcomes, statistical methods may need to account for variation in counts that exceeds what a simple model expects. This is called over-dispersion. In general, ignoring over-dispersion can make uncertainty appear smaller than it is, while a model that accommodates it can produce more appropriate uncertainty estimates. This study’s primary endpoint is a participant count rather than a repeated event-rate analysis, and no count model or dispersion parameter is reported in the registry record. The concept therefore explains a general modeling issue; it does not describe a method used in this trial.

Overall, the available methods information supports a clear description of the endpoint and analysis population, but not a reconstruction of the statistical analysis. The model, handling of repeated or missing observations, confidence-interval procedure and inferential testing plan are not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("0.3 mg BI 754132 - SRD Part", "1 mg BI 754132 - SRD Part", "3 mg BI 754132 - SRD Part", "6 mg BI 754132 - SRD Part")
n      <- c(3, 3, 3, 6)
events <- c(0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  0.3 mg BI 754132 - SRD Part  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  1 mg BI 754132 - SRD Part  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  3 mg BI 754132 - SRD Part  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  6 mg BI 754132 - SRD Part  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures: the primary dose-limiting-event count and secondary safety and pharmacokinetic outcomes for the single and multiple dose parts. The secondary outcomes include drug-related adverse events, ocular adverse events in the study eye, serum concentration measures after a single dose, trough levels before later administrations, and plasma concentrations after the third administration. Multiple outcomes create a general multiplicity issue: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan accounts for the number and ordering of tests. This is a general statistical concern, not evidence that such testing or adjustment occurred in this study.

The registry record lists zero analyses. It does not report a hierarchy of outcomes, multiplicity adjustment, prespecified testing sequence, or inferential results for the primary or secondary outcomes. Whether any multiplicity strategy was planned or used is not reported in the registry record.

The primary treated set is defined as participants who received at least one dose of BI 754132 and were included in the single rising dose part. This population definition identifies who was eligible for the primary endpoint analysis; it does not describe how missing endpoint observations were handled. The record does not report missing-data counts, reasons for missingness, imputation procedures, sensitivity analyses, or whether all treated participants completed the relevant follow-up. Those details are not reported in the registry record.

Because the primary endpoint is not reported, the registry does not allow assessment of how missing observations might affect its result. Nor does it establish whether analysis populations for secondary outcomes matched the primary treated set. The population used for each outcome, beyond the stated primary population, is not reported in the registry record. These gaps limit reproducibility and prevent a full assessment of whether the posted results follow a prespecified analysis plan.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: eye haemorrhage (33.3%), optic ischaemic neuropathy (33.3%), papilloedema (33.3%).

The registry lists serious adverse-event figures separately for five groups: 0.3 mg, 1 mg, 3 mg and 6 mg in the single rising dose part, and 6 mg in the multiple dose part. In those groups, the numbers at risk and affected were, respectively, 3 and 1; 3 and 0; 3 and 0; 6 and 1; and 3 and 2. The registry reports zero deaths in each group. These are descriptive counts, not estimates from a randomized comparison.

For other adverse events, the listed numbers at risk and affected were 3 and 1; 3 and 1; 3 and 3; 6 and 3; and 3 and 2 across those same groups. Serious and other adverse-event categories should be read according to the registry’s labels; the record does not establish that these categories are mutually exclusive or that an affected participant had only one event.

The top serious-event terms are Eye haemorrhage, Optic ischaemic neuropathy and Papilloedema, each listed as 33.3%. These terms and percentages do not establish that BI 754132 caused the events. They also do not answer the primary dose-limiting-event question, whose reported participant count is not available in the registry record. No comparative risk interpretation is warranted from these non-randomized groups.

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

The study’s stated focus was safety, tolerability and pharmacokinetics after single rising intravitreal doses and repeated intravitreal dosing of BI 754132 in participants with geographic atrophy. The design reflects an early-phase, sequential investigation, with no randomization, masking or control group. Its structure can describe the experience recorded in the dose groups, but it does not provide a controlled estimate of a treatment effect.

The posted adverse-event counts indicate that events were recorded in the groups, including serious adverse events in some groups, while the registry reports zero deaths in each group. These descriptive data do not establish that the study drug caused any event, and they do not show whether a participant met the primary dose-limiting-event definition. The primary endpoint result is not reported in the registry record. Therefore, the principal safety question identified by the study cannot be answered from that record’s primary outcome information.

The result does not establish whether BI 754132 reduces geographic atrophy, preserves vision, or improves any other clinical outcome. The primary endpoint is a safety count, not an efficacy measure, and no controlled efficacy comparison is described. The registry lists pharmacokinetic outcomes, but their numerical results are not reported in the registry record. No conclusion about drug exposure can be drawn from the outcome titles alone.

The numbers are also too limited in design and reporting to support a reliable comparison of dose levels. Non-random allocation and sequential enrollment mean that differences among groups could reflect factors other than dose. The registry does not report adjustment for such differences or a statistical analysis of the group contrasts. The serious-event percentages should therefore be treated as descriptive listings, not as evidence of a dose-response relationship.

In general, early-phase studies can contribute information about tolerability and guide later research. That general role does not make a small uncontrolled study definitive. For this trial, the registry record documents the design and some safety counts, but does not report the primary endpoint result, a statistical uncertainty measure, or numerical pharmacokinetic results. The scope of interpretation is consequently narrow.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its question and design need to be kept distinct. It asks about dose-limiting events during dose escalation, but the groups are not randomized controls. A sequence of dose cohorts can be useful for describing observations as dosing proceeds, yet it does not create a fair causal comparison among doses. The design limits what can be inferred even before considering the small group sizes.

The primary endpoint is defined at the participant level and has a stated observation window. Those details matter: counts need a clear denominator, a consistent event definition and a specified period of follow-up. The registry identifies the treated set for the primary outcome, but does not report the count of participants meeting the endpoint. This illustrates why a well-defined endpoint is not enough on its own; the result and its uncertainty are also needed for interpretation.

The trial also separates single-dose escalation from repeated dosing. The multiple dose part uses the 6 mg dose on a different schedule from the single injection groups. Those observations can describe different exposure patterns, but the parts should not be collapsed into a direct dose comparison. Study structure determines which contrasts have a defensible interpretation.

Finally, the record lists serious and other adverse-event counts but no analyses. Descriptive safety reporting and inferential comparison are different tasks. Counts can make the observed events transparent, while a statistical analysis would need to clarify the population, uncertainty, missing data and any comparison strategy. The registry does not report those analytic details. The case underscores the value of reading design, endpoint, population and result together rather than treating a numerical event listing as a stand-alone conclusion.

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 main limitation is that the registry record does not report the primary endpoint result. It defines dose-limiting events and the follow-up window, but does not state how many participants experienced them. Without that count, the central tolerability endpoint cannot be summarized or compared across the single rising dose groups.

The study was non-randomized, sequential, open label and uncontrolled. There is no like-for-like comparator, and apparent differences across dose groups cannot be attributed to dose alone. The registry does not report an adjusted analysis that might address measured differences, nor does it describe baseline characteristics that would help assess comparability.

The enrolled population was 18, with the primary endpoint restricted to the single rising dose part. The dose-group safety counts are small and are reported separately for the single and multiple dose parts. Such counts are descriptive and cannot provide precise comparative estimates on their own. The registry does not report confidence intervals for the primary endpoint.

The registry lists serious adverse-event terms and percentages, but does not provide enough information to connect those terms with the primary dose-limiting-event definition. It also does not report the primary outcome’s missing-data handling, outcome-specific analysis populations beyond the stated treated set, or a statistical analysis plan. Numerical results for the listed pharmacokinetic outcomes are not reported in the registry record.

The study is marked terminated, but the reason for termination is not reported in the registry record. The available information does not support assumptions about why it ended, whether planned follow-up was completed, or whether termination affected data collection. These reporting gaps, together with the uncontrolled design, constrain interpretation to the recorded design features and descriptive safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Test How Well Different Doses of BI 754132 Are Tolerated in Patients With an Advanced Form of Age-related Macular Degeneration Called Geographic Atrophy — NCT04002310.
• Registry record last updated 2023-09-15; status last verified 2023-09.
• Results first posted 2023-09-15.
• 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

NCT04002310 is a phase 1, open-label, non-randomized, uncontrolled study of BI 754132 in participants with geographic atrophy secondary to age-related macular degeneration. It enrolled 18 participants and is recorded as terminated. The design included a sequential single rising dose part at 0.3 mg, 1 mg, 3 mg and 6 mg, and a multiple dose part using 6 mg in three injections separated by 4 weeks.

The primary outcome was the number of treated participants in the single rising dose part with an ocular study-eye or systemic dose-limiting event, followed from administration until the end of the trial, up to 100 days. The primary result and numerical pharmacokinetic results are not reported in the registry record. Descriptive serious and other adverse-event counts are listed by group, with zero deaths reported in each. The registry lists 10 outcome measures and zero analyses. The uncontrolled, non-randomized design does not support a like-for-like causal comparison across dose groups.