Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes (NCT02240706), a randomized phase 2 study. The primary outcome is Number of Patients With Dose Limiting Toxicity (DLT) (Phase I).

2. Clinical Question

3. Trial Design

The registry describes a Phase I/II study of BI 836858 in low or intermediate-1 risk myelodysplastic syndromes with symptomatic anemia. The listed phase is Phase 2, while the trial description and outcomes also identify a Phase I dose-escalation component. The study was randomized, parallel-group, and open-label, with no masking. It was conducted at multiple centres according to its official title.

Phase I investigated BI 836858 monotherapy, including maximum tolerated dose, safety and tolerability, pharmacokinetics, exploratory biomarkers, and efficacy. The posted primary endpoint is a count of participants with dose-limiting toxicity. Results are reported for dose groups of BI 836858 20 mg, 40 mg, 80 mg, 160 mg, and 320 mg. The endpoint population is the MTD evaluation set, defined in the record by having initiated at least one dose and not having been replaced for that evaluation.

Phase II was intended to compare BI 836858 plus Best Supportive Care with Best Supportive Care alone. The registry record does not report results for that comparison. It also does not report the allocation ratio, the number randomized to each Phase II arm, or whether the intended Phase II comparison proceeded as planned.

Enrollment is recorded as 27. The study started on 2015-01-22, had primary completion on 2019-11-18, and is listed as terminated. A reason for termination is not reported in the registry record. These design and status details provide context, but they do not establish the reason the study ended or the findings of the planned Phase II comparison.

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: Subjects were screened for eligibility prior to participation. They attended a specialist site which ensured that they strictly met all eligibility criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: As the study was prematurely discontinued, recruitment of participants into the dose escalation part was not fully completed. No formal MTD was determined.

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 had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With Dose Limiting Toxicity (DLT) (Phase I), measured over From the first administration of BI 836858 to start of the third administration of BI 836858, excluding the day of the third administration of BI 836858, up to 28 days.

The primary endpoint counts participants with dose-limiting toxicity (DLT) in Phase I. The specified observation window runs from the first administration of BI 836858 to the start of the third administration, excluding the day of that third administration, up to 28 days. DLTs are defined using several safety criteria, including certain non-disease-related, non-hematologic adverse events of grade 3 or higher, inability to deliver the assigned full dose in cycle 1 because of drug-related adverse events, specified lack of hematologic recovery, and a drug-related delay in starting cycle 2.

The definition includes exceptions and qualifications. For example, some laboratory abnormalities do not count if they are not considered significant, resolve spontaneously, or recover with appropriate treatment within 5 days. Certain neutrophil-related events do not count if they recover with appropriate treatment within 14 days. The record also specifies thresholds and durations for neutrophil and platelet recovery and a cycle 2 delay criterion. These details matter because the endpoint is determined by protocol-defined rules, not by an unrestricted count of every adverse event.

Counting DLTs by dose is a way to describe early tolerability during dose escalation and inform dose evaluation. The endpoint is not an estimate of comparative efficacy. The registry posts counts by dose group, without a confidence interval or other uncertainty estimate. The full adjudication process and any additional rules used to classify borderline events are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count convey? A count endpoint records how many participants met a defined event criterion. Here, the event is a protocol-defined DLT, and the registry reports a count alongside the number of participants in each dose group. This directly describes what was observed in the MTD evaluation set. It is distinct from a rate or a comparative effect estimate, which would require an explicit denominator and a defined comparison. The registry’s displayed counts can be read within each reported dose group, but they do not provide an adjusted estimate or account for differences between groups.

Why is dose-group interpretation cautious? Dose escalation studies examine safety across dose levels, but the posted counts do not establish that dose alone explains differences between groups. The registry record does not report details of the escalation rule, the sequence in which participants entered dose groups, or the decision process for selecting a dose. The observed counts therefore describe the recorded groups; they should not be read as a randomized comparison among the dose levels.

What would a confidence interval add? In general, a confidence interval expresses the statistical uncertainty around an estimated quantity under specified assumptions. For a count or event proportion, it can convey how much uncertainty remains when the observed group is limited. No confidence intervals are posted for the primary DLT counts. Without them, the reader cannot use the primary results to assess precision through an interval estimate. A zero observed count is still compatible with uncertainty about events that were not observed in the group.

Why does the definition of DLT matter? An endpoint is only interpretable in relation to its operational definition and observation window. The registry’s definition includes selected adverse events, inability to deliver the assigned dose because of drug-related adverse events, hematologic recovery criteria, and treatment-delay criteria. It also lists exceptions and conditions for when particular abnormalities do not qualify. Applying such rules can make a safety endpoint more specific to the trial’s dose-evaluation purpose, but it means the DLT count is not interchangeable with a count of all adverse events. The timing window also limits the endpoint to the stated early period; it does not represent a count over all follow-up.

How does randomization relate to the posted results? Randomization is recorded for the trial, and the design includes a Phase II comparison between BI 836858 plus Best Supportive Care and Best Supportive Care alone. In general, random allocation can support a causal comparison when outcomes are analyzed according to an appropriate plan and relevant data are available. The posted primary results, however, are Phase I dose-group counts. They do not report an effect estimate for the randomized Phase II arms. Allocation ratio, analysis population for the Phase II comparison, and any adjustment methods are not reported in the registry record.

What does the analysis status tell us? The record lists 0 analyses. It therefore does not provide an inferential analysis of the primary endpoint, such as a hypothesis test, a confidence interval, or a model-based estimate. The absence of a posted analysis is not evidence that no analysis was conducted outside the registry; it means that such an analysis is not reported in the registry record. The statistical analysis plan, handling of missing observations, and any interim analyses are also not reported in the registry record.

How should planning calculations be understood? In general, sample-size planning calculations depend on assumptions about the target effect, significance level, allocation, and statistical method. The record describes planning illustrations based on a fraction of an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those assumptions describe illustrations rather than the trial’s own design justification. A trial’s sample-size justification is not reported in the registry record. A planning illustration is not observed power and cannot substitute for a reported analysis of trial outcomes.

What is over-dispersion, in general? Over-dispersion occurs when observed variability is greater than a statistical model expects. In count analyses, it can make standard errors and uncertainty intervals too small if the model does not account for that extra variability. The posted primary outcome is presented as group counts, not as a fitted count model, and the registry record does not report an over-dispersion assessment. This general concept does not imply that over-dispersion was present in this trial.

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("BI 836858 20 mg (Phase I)", "BI 836858 40 mg (Phase I)", "BI 836858 80 mg (Phase I)", "BI 836858 160 mg (Phase I)", "BI 836858 320 mg (Phase I)")
n      <- c(2, 3, 6, 4, 9)
events <- c(0, 0, 1, 0, 2)
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  BI 836858 20 mg (Phase I)  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  BI 836858 40 mg (Phase I)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 836858 80 mg (Phase I)  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  BI 836858 160 mg (Phase I)  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  BI 836858 320 mg (Phase I)  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6

11. Multiplicity, Missing Data and Analysis Populations

The record lists 11 outcome measures, including the primary Phase I DLT endpoint and secondary outcomes concerning transfusion independence, hematologic improvement, hemoglobin increase, response duration, and overall objective response. Eight secondary outcomes are identified as posted. These outcomes involve different clinical events and, in some cases, response timing or duration. When multiple outcomes are examined, the chance of at least one apparently unusual result can increase unless the analysis plan addresses multiplicity. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting these outcomes.

The record lists 0 analyses, and results for the secondary outcomes are not reported in the registry record. No p-values or confidence intervals for those outcomes are available in the posted record. Missing data methods, censoring rules, and any sensitivity analyses are not reported in the registry record. Their absence prevents assessment of how incomplete observations or follow-up were handled.

The primary endpoint population is defined as the MTD evaluation set: patients documented to have initiated at least one BI 836858 dose and not replaced for the MTD evaluation. The criteria for replacement are not reported in the registry record. The analysis populations for the Phase II randomized comparison are also not reported. In particular, the record does not state whether a Phase II analysis would have followed randomized assignment, treatment received, or another population definition.

Because no inferential results are posted, there is no sponsor analysis to compare with a recalculated estimate, and no basis for assessing how missing data or multiple outcomes affected a comparative conclusion.

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: acute coronary syndrome (33.3%), pyrexia (33.3%), cellulitis (33.3%), enterocolitis infectious (33.3%), staphylococcal infection (33.3%).

The registry reports serious and other adverse-event counts separately from the primary DLT outcome. For serious adverse events, the reported affected and at-risk counts are 2 of 3 at BI 836858 20mg, 2 of 3 at 40mg, 3 of 6 at 80mg, 0 of 4 at 160mg, and 6 of 11 at 320mg. For other adverse events, the corresponding counts are 3 of 3, 3 of 3, 6 of 6, 4 of 4, and 9 of 11. Death counts are reported as 1, 0, 1, 0, and 3, respectively. These are descriptive counts and do not establish that an event was caused by treatment.

The adverse-event at-risk counts differ from the denominators in the primary DLT results, and the registry record does not explain the difference. The serious event terms listed are Acute coronary syndrome, Pyrexia, Cellulitis, Enterocolitis infectious, Staphylococcal infection, and Infusion related reaction, each reported as 33.3%. The denominator and counting details for these term percentages are not reported in the registry record, so the percentages should not be converted into participant counts.

These safety summaries are not a randomized comparison. They also do not describe event timing, recurrence, severity beyond the serious classification, or causal attribution for each event.

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

The primary result means that the registry records DLTs in some Phase I dose groups and no DLTs in others during the defined observation period. Specifically, the posted counts are 0 of 2 at 20 mg, 0 of 3 at 40 mg, 1 of 6 at 80 mg, 0 of 4 at 160 mg, and 2 of 9 at 320 mg. The definition is tied to specified toxicity and treatment-delivery criteria, so these results describe the trial’s DLT endpoint rather than all possible safety events.

The counts do not show how BI 836858 compares with Best Supportive Care alone. That planned Phase II comparison has no posted effect estimate in the registry record. The counts also do not establish that BI 836858 caused or prevented any individual event, nor do they establish a dose-response relationship. The groups are not presented as randomized comparisons of doses, and uncertainty intervals are not reported.

The primary endpoint does not establish efficacy. Although the trial’s objectives included exploratory efficacy in Phase I and safety and efficacy in Phase II, results for the listed secondary outcomes and the Phase II comparison are not reported in the registry record. It is therefore not possible from these posted primary results to assess transfusion independence, hematologic response, objective response, or comparative efficacy.

Finally, the status of terminated does not, by itself, explain why the study ended or what its findings imply. The reason for termination and details of the Phase II analysis are not reported in the registry record. The most defensible interpretation is limited to the posted descriptive Phase I DLT counts and the stated definitions used to classify them.

14. Why This Trial Matters Statistically

This trial illustrates the difference between an early dose-escalation endpoint and a randomized comparative endpoint. Phase I asks how many participants meet a defined DLT criterion at each dose during an early treatment window. Phase II was intended to compare BI 836858 plus Best Supportive Care with Best Supportive Care alone. Those are distinct statistical questions, and the Phase I counts cannot stand in for the Phase II comparison.

The endpoint definition also shows why safety counts require context. DLT is not simply any adverse event: the registry specifies grades, treatment relationships, recovery conditions, blood count criteria, and a treatment-delay criterion. A count therefore depends on how the event is defined and on the observation window. Readers should distinguish this endpoint from the broader adverse-event summaries, which use separately reported at-risk counts.

There is an important precision issue as well. The reported groups contain limited denominators, and no uncertainty intervals or inferential analysis are posted for the primary result. The counts are informative as a record of what was observed, but they do not by themselves support precise estimates of underlying event frequency or a comparison among doses.

Finally, the registry record contains a planned randomized Phase II question but no posted result for that comparison. This makes the boundary between design intent and available evidence especially important. The record documents the intended comparison and the Phase I DLT observations; it does not supply a comparative estimate of the planned Phase II outcomes.

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 principal trial-specific limitation is that the posted primary outcome covers the Phase I dose groups, while the planned Phase II comparison is not reported in the registry record. No two-arm estimate, confidence interval, or hypothesis test is posted. The record also lists 0 analyses, limiting review of statistical methods and inferential findings.

For the DLT endpoint, the group counts are accompanied by limited denominators and no uncertainty intervals. The MTD evaluation population is defined, but replacement criteria and the number of participants excluded or replaced are not reported in the registry record. The timing window and detailed DLT criteria are described, but event-level adjudication and classification details are not reported.

The registry lists 11 outcome measures and identifies eight secondary outcomes as posted, but secondary results are not reported in the registry record. Multiplicity procedures, missing-data methods, sensitivity analyses, and the statistical analysis plan are not reported. The reason for termination and any relationship between termination and the availability of Phase II results are also not reported.

For safety, the adverse-event at-risk denominators differ from the primary endpoint denominators, without an explanation in the registry record. The denominator behind the percentages for the serious event terms is not reported. These details limit interpretation of the safety summaries and prevent a direct reconciliation with the primary DLT counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes — NCT02240706.
• Registry record last updated 2020-12-21; status last verified 2020-12.
• Results first posted 2020-12-21.
• 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

NCT02240706 is a Phase I/II, multicentre, open-label, randomized, parallel trial of BI 836858 for low or intermediate-1 risk myelodysplastic syndromes with symptomatic anemia. Phase I investigated BI 836858 monotherapy using dose escalation; Phase II was intended to compare BI 836858 plus Best Supportive Care with Best Supportive Care alone. The record lists enrollment as 27 and status as terminated.

The posted primary endpoint is the number of participants with DLT in the Phase I MTD evaluation set during the specified early treatment period. Counts are reported for five dose groups. The registry record does not report a Phase II comparative result, inferential analyses, or the reason for termination. Secondary outcome results and important details about missing-data handling, multiplicity, and the statistical analysis plan are also not reported in the registry record.