Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (NCT02968563), a non-randomized phase 2 study. The primary outcome is Rate of Complete Response/Complete Remission (CR), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25.

2. Clinical Question

The registry describes a preliminary-efficacy study in adults with relapsed or refractory CLL. Its primary endpoint focuses on complete response, a defined disease-response category, rather than on a comparison of time to progression or survival. The endpoint includes CRi, which allows persistent anemia, thrombocytopenia, or neutropenia attributed to drug toxicity rather than CLL when the other stated criteria are met.

Secondary outcomes included complete response with bone-marrow or peripheral-blood minimal residual disease negativity, overall response rate, and treatment-emergent adverse events, including serious adverse events. Numerical results for these efficacy outcomes are not reported in the registry record. The record therefore defines the clinical question and planned measurements, but does not establish how often participants met the primary response definition.

3. Trial Design

This was a Phase 2, prospective, open-label, multicenter study with parallel treatment groups and non-randomized allocation. The record lists 35 participants enrolled and marks the study as completed. The study began on 2016-12-13, with primary completion on 2019-06-17. Those dates describe the trial record; they do not supply an efficacy result.

Both groups received tirabrutinib and idelalisib. One group also received obinutuzumab. The registry describes tirabrutinib 80 mg once daily and idelalisib 100 mg once daily for up to 104 weeks. In the group with obinutuzumab, that drug was added on a dosing schedule that included doses on Day 1 and subsequent scheduled days. The full schedule is not reported in the registry record. The study summary describes adaptive treatment, active treatment for up to two years, and follow-up after treatment or early discontinuation.

The study summary says a safety run-in included 6 participants per arm before subsequent enrollment. The adverse-event record lists 5 participants at risk in the tirabrutinib-plus-idelalisib group and 30 in the group that also received obinutuzumab. The registry does not explain the difference between those descriptions, so the run-in statement should not be used to infer the final allocation or analysis population.

Because treatment assignment was not randomized and the study was open-label, the arms do not constitute a randomized controlled comparison. The design can describe outcomes observed in each treatment group, but differences between groups may reflect factors other than treatment. The registry record does not report a detailed statistical analysis plan, a sample-size justification, or numerical Week 25 response findings.

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: 35 participants were screened. Randomization was discontinued after implementation of Protocol Amendment 3; all additional participants were enrolled to Arm: Tirabrutinib + Idelalisib + Obinutuzumab.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug.

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: The Full Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug.

6. Primary Endpoint

The registry lists the primary outcome as Rate of Complete Response/Complete Remission (CR), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25, measured over Week 25.

The primary endpoint is the percentage of participants with complete response or complete remission with incomplete bone-marrow recovery at Week 25, assessed by the investigator using modified IWCLL 2008 criteria. The registry defines the numerator as participants achieving CR or CRi by that time point. It identifies the Full Analysis Set as enrolled participants who received at least one dose of any study drug.

As described in the record, CR requires the stated absence of specified disease-related symptoms and findings, along with blood and bone-marrow criteria. These include no lymphadenopathy greater than 1.5 cm, lymphocytes less than 4000/μL, and thresholds for platelets, hemoglobin, and neutrophils. The bone-marrow criteria include a normocellular sample with 30% lymphocytes and no B-lymphoid nodules. CRi uses the stated CR criteria but permits persistent anemia, thrombocytopenia, or neutropenia when unrelated to CLL and related to drug toxicity. The record's wording for the bone-marrow criteria is not further clarified.

A response percentage is a binary-outcome summary: participants are classified according to whether they met the endpoint definition. Such an endpoint can describe how often a defined response was observed at a specified assessment time. It does not, by itself, describe how long a response lasted or establish a causal treatment effect.

The registry lists a 90% confidence interval as the dispersion measure, but neither the response percentage nor the interval is reported in the registry record. Consequently, the precision of the primary efficacy estimate cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a binary percentage: the percentage of participants who achieved complete response or CRi at Week 25. A binary endpoint classifies each participant according to whether a specified event occurred. In this case, the event is meeting the investigator-assessed response definition at the stated assessment time. The record specifies the outcome criteria and the Full Analysis Set, but does not report the number meeting the endpoint or the resulting percentage.

What does a confidence interval communicate?

A confidence interval expresses statistical uncertainty around an estimate. It is not a guarantee that the true value lies within the interval, and it does not correct for limitations such as non-randomized allocation or incomplete outcome reporting. The registry specifies a 90% confidence interval for the primary outcome, but its endpoints are not reported in the registry record. Without those limits and the response estimate, the precision of the primary finding cannot be assessed.

For a percentage, precision depends in part on the number of participants assessed and the number meeting the endpoint. Small groups generally provide less precise estimates than larger groups, all else being equal. This is a general statistical point, not a calculation of precision for this trial. The record lists 35 enrolled participants, but does not report the primary-outcome counts, the number assessed at Week 25, or the extent of missing endpoint data.

Why does allocation matter?

Random allocation is intended to make treatment groups comparable, on average, with respect to measured and unmeasured factors at the start of a study. This trial is recorded as non-randomized. Its parallel groups therefore cannot be assumed exchangeable. A difference in observed outcomes, even if reported, could arise from differences in participant characteristics or care as well as from the treatment regimens. The record does not report a statistical adjustment strategy that could address those concerns.

Open-label means the study was not masked. General methodological considerations include the possibility that knowledge of treatment assignment may affect care, reporting, or assessments. The registry does not report procedures intended to limit those influences. The primary endpoint was assessed by investigators, so the absence of masking is relevant when interpreting a subjective or judgment-dependent assessment. This is a design consideration, not evidence that any particular assessment was biased.

How should the safety counts be understood?

Adverse-event counts are descriptive summaries of participants with events in the groups identified by the registry. They are not automatically treatment-attributable effects. Event interpretation depends on definitions, follow-up duration, exposure, severity, relatedness assessment, and rules for counting multiple events in one participant. The record lists counts at risk and counts affected for serious and other treatment-emergent adverse events, along with death counts, but does not provide all of those details.

Over-dispersion is a general concern when event counts vary more than a simple statistical model expects. It matters especially for count outcomes, where a small number of participants may experience multiple events. The primary endpoint is described as a participant-level percentage, not a count of repeated events. The record does not report a model for repeated adverse events or an analysis of event rates, so over-dispersion cannot be evaluated from the reported summaries.

What can be said about the analysis plan?

The registry names the Full Analysis Set as participants enrolled who received at least one dose of any study drug. It does not describe a separate per-protocol population, a missing-data method, covariate adjustment, multiplicity control, or interim efficacy analysis. These details are not reported in the registry record. It is not appropriate to infer the methods used from the endpoint definition or study phase alone.

The record states that the primary outcome uses a 90% confidence interval, but does not specify the interval construction method in the information available. It also does not provide the observed response effect or the numerical planning illustrations that may accompany the broader statistical presentation. Any sample-size illustration based on a fraction of an observed effect would be a planning exercise, not observed power, and would not represent the trial's original design unless the record established that it did. A sample-size justification for this trial is not reported in the registry record.

Overall, the available methodological details support identifying the outcome type, assessment time, stated population, and broad design. They are insufficient to reproduce or verify the efficacy analysis. The absence of numerical endpoint results and analysis details is central to interpreting the study 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("Tirabrutinib + Idelalisib", "Tirabrutinib + Idelalisib + Obinutuzumab")
n      <- c(5, 30)
events <- c(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  Tirabrutinib + Idelalisib  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Tirabrutinib + Idelalisib + Obinutuzumab  30  2  6.7  0.8  22.1  1.8  21.3  2.0  21.4

11. Multiplicity, Missing Data and Analysis Populations

The study record lists one primary efficacy outcome and several secondary outcomes. The secondary outcomes include complete response with bone-marrow minimal residual disease negativity, complete response with peripheral-blood minimal residual disease negativity, overall response rate, and treatment-emergent adverse events, including serious adverse events. Numerical findings for the secondary efficacy outcomes are not reported in the registry record.

When a study evaluates multiple outcomes, the chance of at least one apparently notable result can increase if each outcome is tested separately without adjustment. Multiplicity methods are general statistical tools used to control or describe that issue. The registry does not report a multiplicity-adjustment strategy, a testing hierarchy, or whether the secondary outcomes were treated as exploratory. No particular approach should be assumed.

The record defines the Full Analysis Set as all randomized or enrolled participants who received at least one dose of any study drug. Because allocation is non-randomized, the relevant wording includes enrolled participants. The record does not state how many participants in that set contributed to the primary endpoint, how participants who discontinued before Week 25 were handled, or how missing assessments were addressed. A missing-data strategy is not reported in the registry record.

These omissions affect interpretation. If participants with unavailable assessments differ from those assessed, a percentage calculated only among observed assessments may not represent the full enrolled population. This is a general concern, not a claim about what occurred in this trial. Without the outcome counts, assessment denominators, and missing-data rules, the response estimate cannot be reconstructed or its sensitivity to missing observations evaluated.

The registry also lists no analyses in its analysis listing. Detailed statistical methods for the primary and secondary outcomes, including any planned interim analyses, are not reported in the registry record. The absence of those details prevents assessment of how the study handled multiple outcomes and incomplete observations.

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: cardiac failure acute (20.0%), nephrolithiasis (20.0%), ureterolithiasis (20.0%), dermatitis allergic (20.0%), coronary artery stenosis (3.3%).

The registry reports serious adverse events for 3 of 5 participants at risk in the tirabrutinib-plus-idelalisib group and 14 of 30 participants at risk in the group that also received obinutuzumab. Other treatment-emergent adverse events affected 5 of 5 and 29 of 30 participants, respectively. One death is listed in each group. These are descriptive participant counts; the record does not establish that the study drugs caused the events or deaths.

The serious-event terms listed with percentages include cardiac failure acute, nephrolithiasis, ureterolithiasis, and dermatitis allergic at 20.0% each, and coronary artery stenosis and colitis at 3.3% each. The record does not provide enough accompanying detail to determine from these percentages alone the event counts, precise denominators, timing, or attribution by treatment group.

These arm summaries should not be read as a randomized safety comparison. The trial was non-randomized, and the groups had different numbers at risk. The registry does not report exposure-adjusted event rates, follow-up by group, or a detailed account of severity and relatedness assessments. The numbers describe what the record lists, but do not establish comparative safety or causation.

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

The registry record establishes that a prospective, open-label Phase 2 study evaluated tirabrutinib and idelalisib, with or without obinutuzumab, in adults with relapsed or refractory CLL. It specifies a Week 25 investigator-assessed complete-response endpoint and gives its criteria. It also reports selected adverse-event counts. Those details describe the study question and some safety observations.

The record does not report the primary response percentage or the stated 90% confidence interval. It therefore does not show how many participants met the primary response definition or how precisely that response rate was estimated. Results for the listed secondary efficacy outcomes are also not reported in the registry record. Neither efficacy nor the magnitude of uncertainty around efficacy can be characterized from these registry entries.

The two treatment groups cannot be interpreted as a controlled test of adding obinutuzumab. Allocation was non-randomized, the group sizes recorded for safety differ, and the registry does not describe adjustment for differences between participants. Any numerical contrast between the arms would be vulnerable to confounding and should not be treated as a causal treatment effect.

The safety counts indicate that adverse events were recorded in both groups, including serious events and deaths. They do not show, on their own, whether events were caused by study treatment, how event risk changed over time, or whether one regimen was safer than another. Additional information on attribution, exposure, follow-up, and event definitions would be needed for those interpretations.

These distinctions are important: a trial design and endpoint definition are not outcome findings, and descriptive safety counts are not proof of causation. The registry record is informative about what the investigators set out to measure and about the safety counts it lists, but it does not provide the numerical efficacy results needed to judge the primary clinical question.

14. Why This Trial Matters Statistically

This study is statistically notable because it asks a defined response question in a population with relapsed or refractory CLL while using a non-randomized, open-label design. The Week 25 endpoint is operationally specified through modified IWCLL 2008 criteria, and its inclusion of CRi acknowledges a distinction between disease response and persistent blood-count abnormalities attributed to drug toxicity. Clear endpoint definitions matter because they determine which participants are classified as having the outcome.

At the same time, the design constrains what can be learned from comparisons between the treatment groups. Randomization is a central means of reducing systematic baseline differences between arms. Without it, group contrasts are descriptive and can be influenced by participant selection and other differences. This is especially relevant where the recorded safety populations are unequal and one regimen adds a drug to the shared combination.

The record also illustrates why reporting the estimate and its uncertainty is essential. A stated endpoint and confidence-interval type do not reveal the observed response. Without the primary percentage, interval bounds, assessment denominator, and missing-data handling, readers cannot evaluate the outcome's precision or reproduce its analysis. The registry's listed safety counts are interpretable as counts, but they do not replace efficacy results.

For biostatisticians and clinical researchers, the study highlights the value of complete outcome reporting alongside transparent analysis methods. The registry record does not report a detailed statistical plan, multiplicity handling, or a sample-size justification. Those omissions limit appraisal of how the planned outcomes were analyzed and how confidently results could be interpreted. The statistical importance lies not in asserting an unreported treatment effect, but in distinguishing the study's estimand and observed summaries from conclusions the available record cannot support.

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 trial-specific limitation in the registry record is the absence of the primary efficacy result. Although the outcome definition and a 90% confidence interval are specified, neither the response percentage nor the interval limits are reported. The number assessed at Week 25 and the primary endpoint numerator are also not reported in the registry record.

The non-randomized allocation and open-label design limit causal interpretation of any between-group contrast. The registry does not report a detailed method for adjusting for baseline differences, nor does it describe blinded endpoint review. Since investigators assessed the primary response, the lack of masking is relevant to the assessment process, although the record does not establish that it affected any result.

The safety counts have different numbers at risk across arms, and the record does not provide exposure-adjusted rates or sufficient follow-up detail for a direct safety comparison. The listed serious-event terms lack enough accompanying information to establish their denominators, timing, and group attribution. The death counts are reported without details that would establish their cause or relationship to treatment.

The registry does not report how missing Week 25 assessments or discontinuations were handled, nor does it report a multiplicity strategy or a detailed analysis plan. The study summary describes an adaptive treatment period and a safety run-in, but the record does not explain how those features related to the final efficacy analysis. The stated safety run-in of 6 participants per arm also does not align transparently with the at-risk group counts of 5 and 30; the record does not clarify the relationship.

Finally, numerical results for the secondary efficacy outcomes are not reported in the registry record. These limitations mean the available information supports a description of design and selected safety summaries, but not reconstruction of the primary analysis or a comparative efficacy conclusion.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) — NCT02968563.
• Registry record last updated 2022-01-21; status last verified 2021-12.
• Results first posted 2020-07-01.
• 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

NCT02968563 is a completed, prospective, open-label, multicenter Phase 2 study in adults with relapsed or refractory CLL. It used non-randomized parallel allocation and enrolled 35 participants. The treatment groups received tirabrutinib and idelalisib, with obinutuzumab added in one group.

The primary outcome was the investigator-assessed percentage achieving complete response or CRi at Week 25 under modified IWCLL 2008 criteria, with a 90% confidence interval specified. The primary response result and interval are not reported in the registry record. The registry lists serious adverse events in 3 of 5 participants in one group and 14 of 30 in the other, other treatment-emergent adverse events in 5 of 5 and 29 of 30, and 1 death in each group.

Non-randomized allocation limits arm-to-arm causal interpretation. Statistical details on missing data, multiplicity, and the primary analysis are not reported in the registry record.