Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL (NCT03045328), a na phase 2 study. The primary outcome is Complete Response (CR).

2. Clinical Question

3. Trial Design

This was an open-label, non-randomized phase 2 study of ibrutinib with venetoclax in relapsed or refractory CLL or SLL. The registry identifies a single-group model and no allocation method. The study summary describes it as a two-center evaluation of the safety and efficacy of concurrent therapy. Because there is one treatment group and no randomized control group, the design supports describing outcomes among participants receiving the combination, but it does not provide a randomized estimate of how outcomes compare with another treatment.

The registry reports enrollment of 22. Participants received ibrutinib and venetoclax in the same treatment group. Ibrutinib was scheduled to begin by mouth once daily on week 1 day 1; venetoclax was scheduled to begin by mouth once daily on week 9 day 1. The treatment description states that ibrutinib continued in the absence of disease progression or unacceptable toxicity and that venetoclax continued up to week 61 day 7. The available treatment description ends before its final condition is complete, so that detail is not reported in the registry record.

The primary outcome was complete response, assessed at 62 weeks. The registry lists eight outcome measures and names duration of response, minimal residual disease, overall response, overall survival, progression-free survival, and time-to-progression among the secondary outcomes. Although the record indicates that there are no posted analyses, it does not provide the primary complete-response count or a statistical comparison. Some participants withdrew consent before the primary assessment; the number with endpoint data is not reported in the registry record.

The study started on 2017-09-26, reached primary completion on 2020-05-19, and is marked completed. Those dates describe the registered study timeline; they do not supply an endpoint result or explain the analysis procedures.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Some participants withdrew consent before the assessment.

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.

6. Primary Endpoint

The registry lists the primary outcome as Complete Response (CR), measured over 62 weeks.

The primary endpoint is the number of participants who achieved complete response (CR), assessed by investigators using International Workshop on Chronic Lymphocytic Leukemia criteria. The assessment timeframe is 62 weeks. The criteria described in the registry include no lymphadenopathy greater than 1.5 cm, blood lymphocytes below 4,000/µL, no hepatomegaly, no splenomegaly, and normocellular bone marrow with fewer than 30 lymphocytes and no B lymphoid nodules.

A complete-response count is a binary-outcome summary: each assessed participant is classified as having met or not met the response definition, and the endpoint reports the count meeting it. It is used to describe how many participants reached a defined disease-response state by the specified assessment time. The count by itself does not show the precision of the estimate, because the registry record gives no dispersion measure or confidence interval. Nor does it quantify a treatment effect relative to a control group.

Some participants withdrew consent before assessment. The number assessed and the number achieving CR are not reported in the registry record. Consequently, the endpoint definition is available, but the observed primary result and its uncertainty cannot be evaluated from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a phase 2, open-label, non-randomized, single-group study. The statistical interpretation is limited by the outcome information recorded: the primary endpoint is a participant count, but its observed value is not reported, and no analyses are posted for the outcomes. The explanations below describe general statistical concepts and do not imply that particular methods were used in this study.

What does a participant count tell readers?

A count records how many people in an assessed group met an outcome definition. For a binary endpoint such as complete response, each assessed participant is classified according to whether the criteria were met. The count is meaningful only alongside the number assessed and a clear account of how missing assessments were handled. In this record, enrollment is reported as 22 and some participants withdrew consent before assessment, but the assessment denominator and CR count are not reported in the registry record.

A count alone does not show sampling uncertainty. In general, uncertainty can be represented with a confidence interval for a proportion or another suitable estimate. The interval's interpretation depends on the analysis and assumptions used. No confidence interval or other dispersion measure is reported for the primary outcome, so readers cannot evaluate the precision of a CR estimate from the registry entry.

Why does the study design matter?

Random allocation, when used, helps create groups that can be compared by reducing systematic differences at baseline on average. This study is identified as non-randomized and single-group, with no comparator arm reported. Its outcome summaries can describe what was observed among participants receiving the combination, but they cannot isolate a comparative treatment effect. This is a general design principle; it does not determine the direction or size of any unreported outcome.

Open-label means the record does not describe masking. In general, knowledge of treatment assignment can influence subjective assessments or reporting, particularly where an endpoint requires clinical judgment. The primary endpoint is based on investigator assessment using stated criteria. The registry does not report procedures intended to address possible assessment bias, so those procedures should not be assumed.

What would an analysis plan clarify?

A statistical analysis plan commonly specifies the outcome definition, analysis population, handling of missing data, statistical model or summary method, and any planned hypothesis tests or multiplicity approach. These choices affect how results should be interpreted. The registry record does not report a statistical plan, an analysis population, or analyses for the listed outcomes. It is therefore not possible to determine from this record whether a particular test, adjustment, imputation approach, or prespecified analysis was used.

For a time-to-event outcome, general methods may account for differing follow-up duration and censor participants whose event status is not observed through the end of follow-up. Such methods require information about event times and censoring. The registry lists duration of response, overall survival, progression-free survival, and time-to-progression, but does not provide their analysis results or methods in the record. Their names alone do not show which definitions, censoring rules, or models were used.

How should missing outcomes be considered?

Missing outcome data can affect interpretation when the participants with observed data differ from those without observed data. The record specifically notes that some participants withdrew consent before the primary assessment. It does not report the number affected, reasons beyond withdrawal of consent, subsequent outcome information, or the method used to handle missing assessments. General approaches may include defining an analysis population and conducting sensitivity analyses under different assumptions, but the record does not say whether these approaches were used.

What does multiplicity mean in general?

When a study evaluates multiple outcomes or makes multiple statistical comparisons, the chance of at least one false-positive finding can increase if each test is interpreted separately at a conventional threshold. A prespecified testing hierarchy or multiplicity adjustment can address this issue, depending on the study objectives. The registry lists eight outcome measures and does not report analyses or a multiplicity procedure. The presence of multiple outcomes does not establish that multiple hypothesis tests were performed, and no such testing strategy should be inferred.

These general concepts explain why endpoint counts, denominators, uncertainty estimates, analysis populations, and analysis methods are needed to interpret clinical results. For this trial, the registry provides the primary outcome definition and selected safety counts, but does not report the primary response count or the statistical analyses needed to assess its precision or compare it with another group.

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("Treatment (Ibrutinib, Venetoclax)")
n      <- c(20)
events <- c(12)
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  Treatment (Ibrutinib, Venetoclax)  20  12  60.0  36.1  80.9  38.7  78.1  38.4  78.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures, including complete response as the primary endpoint and several secondary outcomes: duration of response, minimal residual disease, overall response, overall survival, progression-free survival, and time-to-progression. It reports no analyses for these outcomes. A multiplicity strategy, such as a testing hierarchy or adjustment for multiple statistical tests, is not reported in the registry record. The list of outcomes alone does not show that each was tested or establish how any tests were interpreted.

Missing data are relevant to the primary endpoint because the record states that some participants withdrew consent before assessment. It does not report how many participants withdrew before the assessment, how many had an evaluable endpoint, or how missing CR outcomes were handled. The primary response count and the analysis population are also not reported. As a result, the relationship between enrollment and the endpoint denominator cannot be assessed.

In general, missingness can affect an estimate when the probability of having an observed outcome is related to participant characteristics or outcome status. Statistical approaches may define analysis populations, make assumptions about missing outcomes, or examine sensitivity to alternative assumptions. These are general possibilities, not methods that can be attributed to this study. The registry record does not report imputation, sensitivity analyses, or a prespecified missing-data strategy.

Without an endpoint count, denominator, missing-data method, or analysis plan, readers cannot determine the effect of withdrawals on the reported primary result. The record also does not report whether the secondary outcomes were analyzed in a common population or under outcome-specific rules.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: aspiration (13.6%), sepsis (9.1%), febrile neutropenia (4.5%), mastoiditis (4.5%), fracture skull (4.5%).

The registry reports one treatment group for adverse events. Serious adverse events were reported in 10 of 22 participants, and other adverse events were reported in 22 of 22 participants. Deaths are reported as zero. These are descriptive counts from the registry record; they are not comparative estimates against a control group.

The listed serious adverse-event terms include aspiration at 13.6%, sepsis at 9.1%, febrile neutropenia at 4.5%, mastoiditis at 4.5%, fracture skull at 4.5%, and hematoma at 4.5%. These percentages are registry entries for the listed terms. The record does not provide a comparison group, event-level details, or an analysis of whether events were caused by treatment. A reported adverse event during a study should not be interpreted by itself as evidence of causation.

Serious adverse events and other adverse events are distinct reporting categories. Their counts should be read as separate summaries rather than added together: the record does not establish that the categories represent mutually exclusive participants. The safety figures also do not give detail about severity beyond the serious-event classification, timing, duration, recurrence, or management. Further safety detail is not reported in the registry record.

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

The record establishes that a phase 2, open-label, non-randomized, single-group study evaluated ibrutinib with venetoclax in relapsed or refractory CLL or SLL. It describes the treatment schedule, identifies complete response at 62 weeks as the primary endpoint, and provides the criteria used for investigator assessment. It also reports selected adverse-event counts and terms.

It does not report how many participants achieved complete response. It also does not report an uncertainty estimate for that endpoint, an analysis population, or the methods used to address withdrawals before assessment. The response result therefore cannot be characterized as frequent, infrequent, precise, or imprecise based on the registry record.

The single-group design does not provide a randomized comparison. Even if a response count were available, a count in one treatment group would not by itself show how outcomes differ from those under another treatment. The record cannot support a comparative conclusion about efficacy or a causal conclusion that the combination produced any reported outcome.

The safety figures describe events recorded in the treatment group, including serious events in 10 of 22 participants and other adverse events in 22 of 22 participants. They do not establish that treatment caused those events, and they do not allow direct comparison with another treatment group. The record reports zero deaths in the adverse-event summary but does not provide additional details needed to interpret the timing or context of that figure.

In short, the registry entry supports a description of the trial's design, endpoint definition, and selected safety reporting. It does not supply the primary efficacy result or the statistical details needed to judge its uncertainty, missing-data sensitivity, or comparative meaning. Any stronger interpretation would require information not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation depends on more than an endpoint definition. A primary outcome can be clearly specified—in this case, a count of participants meeting investigator-assessed complete-response criteria at 62 weeks—while the result itself remains unavailable. Without the count, denominator, and uncertainty estimate, readers cannot evaluate the size or precision of the observed response.

Its single-group design also illustrates the distinction between describing an outcome and estimating a comparative effect. A treatment-group outcome can be clinically and scientifically informative as a description, but it does not provide a randomized contrast. Design features determine which questions can be answered, regardless of how clearly an endpoint is defined.

The registry notes withdrawals before primary assessment but does not report the number affected or how the missing assessments were handled. This makes endpoint completeness and sensitivity to missing data important interpretive issues. The record also lists multiple outcome measures without reporting analyses or a multiplicity approach. Those omissions do not establish that the study used inappropriate methods; they mean the statistical approach cannot be evaluated from the registry entry.

Finally, the safety summary distinguishes serious from other adverse events and reports selected terms with percentages. Those figures should be read descriptively, not as causal or comparative estimates. Together, these features make the study a useful example of how registry records can define questions and describe design while leaving important result and analysis details unreported.

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 primary limitation for interpreting efficacy is that the registry record does not report the primary complete-response count. Although the endpoint definition and assessment timeframe are stated, the observed result, denominator, and uncertainty are unavailable. Some participants withdrew consent before assessment, and the record does not report the number affected or how their missing outcomes were handled.

The study is described as non-randomized and single-group, with no control arm reported. This prevents a direct randomized comparison and limits what can be inferred about differences between the combination and other treatment options. The open-label design is also relevant for investigator-assessed outcomes, while procedures addressing potential assessment bias are not reported in the registry record.

The registry does not report an analysis plan, analysis population, statistical tests, confidence intervals, or a multiplicity procedure. It lists secondary outcomes but does not provide their analysis results. Therefore, it is not possible to assess the statistical uncertainty of the primary endpoint, the handling of secondary outcomes, or the robustness of findings to analysis choices.

The safety summary provides selected counts and terms but does not report additional event detail such as timing, duration, recurrence, or attribution. It has no comparator group for assessing relative safety. These limitations concern what can be concluded from the registry record; they do not establish that additional information was not collected or analyzed outside the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL — NCT03045328.
• Registry record last updated 2021-09-29; status last verified 2021-09.
• Results first posted 2021-09-29.
• 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 an open-label phase 2, non-randomized, single-group study of ibrutinib with venetoclax in relapsed or refractory CLL or SLL. Enrollment was 22. Ibrutinib began on week 1 day 1 and venetoclax on week 9 day 1, both by mouth once daily as described in the record.

The primary endpoint was the number of participants achieving complete response by investigator assessment at 62 weeks using International Workshop on Chronic Lymphocytic Leukemia criteria. The registry record does not report the CR count, its denominator, or an uncertainty estimate. Some participants withdrew consent before assessment, and missing-data handling is not reported.

The safety summary reports serious adverse events in 10 of 22 participants, other adverse events in 22 of 22, and zero deaths. The record does not report a comparator or analyses for the outcomes. It is marked completed, with primary completion on 2020-05-19.