BI836826 Dose Escalation in Relapsed Chronic Lymphocytic Leukaemia (CLL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BI836826 Dose Escalation in Relapsed Chronic Lymphocytic Leukaemia (CLL) (NCT01296932), a na phase 1 study. The primary outcome is Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs).

2. Clinical Question

The trial addressed an early-stage development question: whether BI 836826 could be administered at escalating dose levels to adults with advanced, relapsed chronic lymphocytic leukaemia, with attention to safety and tolerability. Its primary endpoint was a count of participants with dose-limiting toxicities, rather than an estimate of comparative benefit against another treatment.

The registry describes secondary outcomes covering changes in peripheral blood lymphocytes, haemoglobin, platelets and neutrophils; best overall response under International Workshop on Chronic Lymphocytic Leukemia criteria; progression-free survival; and failure-free survival. These outcomes give a broader description of what the trial planned to assess, but their numerical results are not reported in the registry record available for this analysis.

3. Trial Design

This was a phase I, open-label, dose-escalation trial of BI 836826 in patients with advanced chronic lymphocytic leukaemia. It is recorded as a single-group study with no masking and no randomized allocation. The registry lists enrollment of 37 participants. The intended population was adults whose disease had relapsed after at least two prior treatment regimens.

Participants were assigned to dose groups receiving BI 836826, with listed dose levels ranging from 1 Milligram through 800 Milligram. Because there was no randomized comparator, differences in event counts between dose groups cannot be interpreted as randomized treatment effects. Dose groups may differ in participant characteristics, exposure or other features, and the registry record does not establish that the groups are otherwise comparable.

The primary endpoint concerns dose-limiting toxicities during the 14 days after first administration, described as the maximum tolerated dose evaluation period. The endpoint population is restricted to those who received at least one dose and were not replaced for the maximum tolerated dose evaluation. This is not necessarily identical to the full enrollment population.

The registry records the trial as completed. Further details about the dose-escalation decision rules, cohort replacement procedures beyond the endpoint population definition, planned dose increments, stopping criteria, and sample-size justification are not reported in the registry record. The record therefore supports a description of the broad design and the stated endpoint, but not a reconstruction of the full operational protocol or the reasoning used to select the dose levels.

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 patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The maximum tolerated dose (MTD) evaluation set: This includes all patients who were documented to have received at least one dose of trial medication and were not replaced for the MTD evaluation.

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 patients who received at least one application of the drug BI 836826.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With Dose-Limiting Toxicities Adverse Events (DLTs), measured over 14 days after first administration of BI836826 (MTD evaluation period).

The primary endpoint is the number of participants with dose-limiting toxicities. It is assessed during the 14 days after the first administration of BI 836826, identified as the maximum tolerated dose evaluation period. The relevant population comprises patients documented as having received at least one dose and not replaced for the maximum tolerated dose evaluation.

The registry defines dose-limiting toxicities as drug-related non-haematologic adverse events of Common Terminology Criteria for Adverse Events Grade 3 or higher, with infusion-related reactions associated with BI 836826 administration excluded. Complications due to haematologic adverse events were also considered dose-limiting toxicities and were added in more detail in a later amendment.

In dose-escalation research, this kind of endpoint is used to describe acute tolerability at the doses being studied and to inform decisions about dose progression. It focuses on a defined assessment window and a specified set of events; it does not capture every possible harm or establish a comparative safety profile. The registry’s numerical result for the primary endpoint is not reported in the registry record. Consequently, the endpoint definition can be described, but the number of participants meeting it cannot be summarized from the recorded information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a phase I, open, single-group dose-escalation study. Its primary outcome is a participant count, not a continuous measurement or a time-to-event estimate. That choice is aligned with the stated endpoint: whether a participant met the protocol definition of dose-limiting toxicity during the specified evaluation period. The record does not provide a numerical primary outcome result, an effect estimate, or an uncertainty interval.

What does a participant count convey?

A count records how many people in a defined group experienced the event of interest. Its interpretation depends on knowing who was eligible for inclusion, how the event was defined, and what period was assessed. Here, the primary population is the maximum tolerated dose evaluation set, and the primary window is 14 days after first administration. The registry further defines which adverse events qualify as dose-limiting toxicities. These restrictions matter: the primary count is not a count of every adverse event during the full trial, and it is not necessarily a count among everyone enrolled.

For the adverse-event summaries, each dose group has an at-risk count and a count of affected participants. Reporting both lets the reader see the group size alongside the event count. With small groups, each participant represents a meaningful part of the group, so the counts may be unstable as estimates of how often an event would occur in a larger population. The record does not report confidence intervals for these summaries.

Why are the dose groups not a controlled comparison?

A dose-escalation study can display event counts separately by dose, but a difference between those counts is not automatically evidence of a dose effect. This trial has no randomized allocation and no separate comparator arm. The dose groups therefore do not have the protection against systematic differences that randomization can provide. In addition, group sizes are limited, and the record does not report adjustment for differences among participants. A trend across groups, even if suggested by a visual display, would remain descriptive rather than a causal estimate.

Open-label conduct means treatment assignment and study participation were not masked. For an event defined by clinical assessment, awareness of the treatment can be relevant to how events are observed or recorded. The registry does not report independent blinded adjudication of adverse events, so no such procedure should be assumed.

What does the endpoint definition contribute?

The threshold of drug-related non-haematologic events at Common Terminology Criteria for Adverse Events Grade 3 or higher narrows the endpoint to serious toxicity by the stated severity criterion. Infusion-related reactions associated with BI 836826 administration are excluded from that non-haematologic definition. The record also says complications due to haematologic adverse events were considered and were described in more detail in a later amendment. The amendment’s full wording, timing, and effect on endpoint classification are not reported in the registry record.

These details are important when interpreting whether a count is comparable across studies: differences in assessment windows, event definitions, severity thresholds or analysis populations can lead to different counts even when the underlying clinical experience is similar. The present record supplies a defined window and criteria, but it does not report enough protocol detail to verify how every borderline event was handled.

How should uncertainty and planning calculations be understood?

A confidence interval is a range expressing statistical uncertainty around an estimate under a specified method. In general, wider intervals indicate less precision, while narrower intervals indicate greater precision. No confidence interval for the primary endpoint is reported in the registry record, and the registry entries do not support deriving one.

Any sample-size illustrations associated with the results are planning exercises based on an observed effect and stated assumptions, not observed properties of this phase I trial. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as fractions of the observed effect. For non-time-to-event outcomes, such illustrations are expressed as participants per arm for a specified power; time-to-event illustrations use a total event count. These calculations do not turn the current single-group study into a two-arm comparison, and they are not evidence that the trial had a particular probability of detecting an effect. The registry’s own sample-size justification is not reported in the registry record.

The record reports 0 analyses. It does not report a statistical analysis plan, hypothesis tests, multiplicity procedures, missing-data methods, or inferential estimates for the listed outcomes. As a result, interpretation should remain at the level of the definitions and descriptive event counts actually recorded, rather than implying unreported modeling or testing.

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 836826 1 Milligram", "BI 836826 3 Milligram", "BI 836826 9 Milligram", "BI 836826 25 Milligram", "BI 836826 50 Milligram", "BI 836826 100 Milligram")
n      <- c(3, 3, 6, 5, 3, 3)
events <- c(0, 0, 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  BI 836826 1 Milligram  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 836826 3 Milligram  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 836826 9 Milligram  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  BI 836826 25 Milligram  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  BI 836826 50 Milligram  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 836826 100 Milligram  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety outcome and secondary outcomes involving blood counts, overall response, progression-free survival, and failure-free survival. It records 9 outcome measures but 0 analyses. A list of outcomes is not the same as a report of which outcomes were analyzed, which comparisons were planned, or how results were interpreted.

Multiplicity arises when several outcomes or comparisons are tested: the chance of at least one apparently noteworthy result can increase if no adjustment or hierarchy is used. Whether any correction, prespecified hierarchy, or other multiplicity strategy was planned is not reported in the registry record. No inferential results are available to assess that issue directly.

The registry identifies the maximum tolerated dose evaluation set for the primary endpoint, including patients who received at least one dose and were not replaced for that evaluation. It does not report the number in that population, the number excluded or replaced, or whether the secondary outcomes used the same population. The reasons and handling of missing outcome data, incomplete assessments, or withdrawals are also not reported in the registry record.

These omissions limit assessment of whether the analysis population matched the intended population and whether participants with incomplete follow-up could have influenced the reported summaries. No imputation approach, censoring rule for time-to-event outcomes, or sensitivity analysis is reported. The available record therefore supports neither an assumption that data were complete nor a claim about how missing observations were handled.

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: haemolytic anaemia (33.3%), neutropenia (33.3%), bundle branch block right (33.3%), left ventricular failure (33.3%), pyrexia (33.3%).

The serious adverse-event summaries give, for each dose group, the number of participants at risk and the number affected. Read them as descriptive counts within the listed groups, not as comparisons against a control group. For example, the registry records 4 of 6 participants affected in the 9 Milligram group and 5 of 6 in the 200 Milligram group; these counts alone cannot establish why the events occurred or whether risk differs by dose.

The record lists Haemolytic anaemia, Neutropenia, Bundle branch block right, Left ventricular failure, Pyrexia, and Respiratory tract infection as top serious adverse-event terms, each at 33.3%. The figures are presented as registry summaries; the record does not clarify in this information whether participants could contribute to multiple terms. The individual terms should therefore not be added together or treated as mutually exclusive categories.

For every dose group, the registry records 0 deaths. This is a description of the recorded study experience, not evidence that the risk of death is absent. The registry also reports other adverse events separately, with all listed participants at risk affected in each group. Serious-event and other-event summaries represent different categories and should not be conflated.

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

The record establishes that BI 836826 was studied in an open phase I dose-escalation trial involving adults with relapsed chronic lymphocytic leukaemia and that the registry recorded 37 participants enrolled. It specifies a primary endpoint based on dose-limiting toxicities during the 14 days after first administration, with a defined evaluation population and event criteria. It also gives descriptive serious and other adverse-event counts by dose group.

However, the numerical result for the primary dose-limiting toxicity endpoint is not reported in the registry record. The secondary outcome results are also not reported in the registry record. Therefore, the recorded information does not establish how many participants met the primary endpoint or what the outcomes were for blood counts, response, progression-free survival, or failure-free survival.

The adverse-event counts show the numbers recorded in each small dose group, but they do not show what would have occurred under a different treatment or without BI 836826. Since the trial was not randomized and had no control group, they cannot be interpreted as comparative treatment effects. Counts across dose levels are descriptive and do not, by themselves, establish a causal relationship between dose and adverse events.

More generally, a safety-focused phase I study and its registry record answer narrower questions than a controlled efficacy study. The definitions and observed counts can help describe what was tracked, but the absent primary endpoint result and unreported analysis details limit conclusions about the full safety profile. The information does not justify a claim that BI 836826 is effective, ineffective, safe, or unsafe. It describes the registry record and its limits, not a basis for medical decisions.

14. Why This Trial Matters Statistically

This trial is statistically notable because its central question concerns event counts during dose escalation, rather than a treatment effect estimated against a control group. That distinction affects what can be learned from the data. A count of dose-limiting toxicities can describe the events meeting a specified definition in a defined window, but without a comparator it cannot distinguish treatment-related risk from background events or other explanations.

The registry’s dose-group summaries also illustrate why denominators matter. The number affected is interpretable only alongside the number at risk in the same group. Here, the groups are small, so a single participant’s event status can materially change the apparent pattern. Descriptive counts are useful for reporting what occurred, but they are not precise estimates of event rates in a wider population.

Outcome definitions and analysis populations are equally important. The primary endpoint excludes infusion-related reactions from its specified non-haematologic criteria, includes a defined severity threshold, considers haematologic complications, and applies to a maximum tolerated dose evaluation set. Those choices shape the count and should accompany any interpretation of it.

Finally, the registry record has an important reporting limitation: the primary endpoint result is not reported, and the record lists 0 analyses. The study design and adverse-event summaries can still be described, but missing results and unreported statistical procedures restrict the strength and scope of statistical conclusions. This is a useful reminder that registry design information, outcome definitions, and numerical results are distinct parts of evidence; completeness in one does not substitute for another.

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 lack of a randomized comparator is a central limitation. The trial’s single-group dose-escalation design does not support a like-for-like control comparison, and differences among dose groups should not be interpreted as causal dose effects. Open-label conduct also means masking cannot be assumed for treatment administration or assessment.

The group sizes in the adverse-event summaries are small, ranging from 3 to 6 participants. Counts from groups of this size are descriptive and provide limited precision. The registry does not report confidence intervals for the event summaries or numerical results for the primary endpoint, so the precision of the principal safety outcome cannot be assessed.

The endpoint population is defined, but its size and its relationship to the full enrollment of 37 are not reported. The record does not provide details on replacements, exclusions, missing assessments, or follow-up completeness. The full dose-escalation rules, statistical analysis plan, sample-size justification, and handling of multiplicity are also not reported in the registry record.

The primary toxicity definition includes specific severity and event-category rules, with a later amendment adding more detail about haematologic complications. The record does not provide the full amendment history or enough information to determine how changes affected event classification. Finally, secondary outcomes are listed without numerical results, limiting interpretation beyond the recorded adverse-event summaries and trial design.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: BI836826 Dose Escalation in Relapsed Chronic Lymphocytic Leukaemia (CLL) — NCT01296932.
• Registry record last updated 2020-08-20; status last verified 2020-08.
• Results first posted 2020-08-20.
• 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

The registry describes a completed phase I, open, single-group dose-escalation trial of BI 836826 in adults with relapsed chronic lymphocytic leukaemia after at least two prior treatment regimens. Enrollment is recorded as 37. The listed dose groups range from 1 Milligram to 800 Milligram, with no randomized comparator.

The primary outcome is the number of participants with dose-limiting toxicities during the 14 days after first administration, assessed in the maximum tolerated dose evaluation set. Its numerical result is not reported in the registry record. Serious adverse-event counts are listed by dose group, and 0 deaths are recorded in each group. Secondary outcomes include blood-count changes, overall response, progression-free survival, and failure-free survival, but their results are not reported in the registry record.

The record lists 9 outcome measures and 0 analyses. Details of the statistical analysis plan, multiplicity handling, missing data, and sample-size justification are not reported in the registry record.