Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients. (NCT02315768), a na phase 1, phase 2 study. The primary outcome is Safety, Tolerability and Dose Limiting Toxicity (DLT) of Ibrutinib in Combination With Obinutuzumab.

2. Clinical Question

3. Trial Design

The registry record describes a phase Ib/II, single-group study of ibrutinib combined with GA101 (obinutuzumab) for previously untreated CLL. The target population was described as people over 65 years of age or people with comorbidities that precluded chemotherapy-based treatment. Enrollment was 32. The record lists the study as completed and identifies the University of California, San Diego as sponsor.

The study began on 2015-08-26, and the primary completion date is listed as 2022-04-18. The intervention description specifies ibrutinib 420 mg orally once daily for up to 6 cycles and GA101 by intravenous infusion for up to 6 cycles, with GA101 cycles described as 28 days. The registry text gives only part of the GA101 administration schedule, so the full regimen cannot be reconstructed from this record.

There is no randomized or parallel control group described. Allocation is listed as not applicable, masking as none, and the model as single group. These design features mean that the posted information describes outcomes among participants receiving the combination; it does not establish a within-trial contrast against a different treatment. Any comparison with outcomes from other settings would require information not reported in the registry record and would not be a randomized comparison.

The record lists two outcome measures and no analyses. It does not report the planned statistical analysis, sample-size justification, interim analyses, analysis populations, or a detailed protocol for defining the primary outcome. The sample-size planning assumptions elsewhere associated with this record describe a two-arm illustration, while the study itself is identified as single group. Those assumptions should not be read as a description of the study's actual design or as evidence of observed power.

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

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 Safety, Tolerability and Dose Limiting Toxicity (DLT) of Ibrutinib in Combination With Obinutuzumab, measured over 4 weeks.

The primary outcome title refers to safety, tolerability and dose-limiting toxicity (DLT) of ibrutinib in combination with obinutuzumab. Such outcomes are used in early-phase research to describe adverse effects and whether the treatment regimen can be administered as intended. In general, a DLT is an adverse effect defined by a study protocol as sufficiently important to affect dose or treatment decisions. The protocol definition, assessment rules and corresponding result are not reported in the registry record.

The endpoint fields are not fully aligned: the title concerns safety, tolerability and DLT, while the description refers to remission rate after discontinuation of ibrutinib in people treated with the combination. The listed timeframe is 4 weeks, and the outcome is expressed as a count of participants. The record does not clarify how remission was defined, how the post-discontinuation period was handled, or whether the description and title refer to the same measurement. This matters because safety events and remission are different outcome concepts and require different definitions and interpretation.

The primary outcome result is not reported in the registry record. Consequently, the posted information does not establish a DLT count, a remission rate, or the precision of either estimate. The general purpose of these measures can be explained, but the missing operational definition and outcome result prevent a substantive interpretation of the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count convey?

The primary outcome is encoded as a count of participants, and the safety information also gives participant counts. In general, a count states how many people meet an outcome definition within the group assessed. A count is not automatically a rate: a rate or proportion requires a clearly defined denominator and an assessment of which participants were eligible for the outcome. The safety entries identify 32 participants at risk for serious and other adverse events, while the primary outcome result and its analysis population are not reported in the registry record.

For binary outcomes, each participant is generally classified according to whether the event or condition occurred during a defined observation period. The interpretation depends on the event definition, time window, and handling of incomplete observation. If these details are unclear, even a correctly recorded count may not answer the intended clinical question. In this study, the primary outcome title and description differ, and the record does not provide a protocol definition that reconciles them.

Why does the single-group design matter?

In general, a comparison between groups helps distinguish differences associated with treatment assignment from other influences, especially when assignment is randomized. This study is listed as single group, with allocation not applicable and no masking. Its posted outcomes describe participants receiving the combination, not a randomized contrast. The data therefore cannot by themselves establish what would have happened to comparable participants under another treatment or without the combination.

Without a concurrent comparator, changes in disease status or adverse events may reflect treatment, underlying disease, other care, participant characteristics, or the way outcomes were assessed. This is not a numerical adjustment that can be recovered from the posted counts. The registry record reports no analyses that would address such factors, and it does not report an external comparison. The proper scope is descriptive rather than comparative.

What can be inferred from a confidence interval?

As a general statistical concept, a confidence interval expresses uncertainty around an estimate under a specified model and procedure. A narrower interval indicates greater precision under those assumptions; a wider interval indicates more uncertainty. An interval does not resolve bias from study design, unclear outcome definitions, missing data, or incomplete reporting. No confidence intervals or other precision measures for the primary outcome are reported in the registry record.

For a binary endpoint, the observed count and denominator are important inputs to an estimate, but the meaning of that estimate still depends on how the endpoint was defined and who was included. Here, the primary outcome has no posted result, so its estimate and precision cannot be assessed. The safety counts can be read descriptively, but the record does not report corresponding intervals or detailed event timing.

How should the planning illustration be understood?

The sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They also specify that the effect to detect is a stated fraction of the observed effect. These are assumptions for an illustration, not a report of the trial's own design justification. The trial itself is identified as single group, so the two-arm equal-allocation assumption does not describe its listed design.

In general, a sample-size calculation estimates how many observations a proposed design may need to detect a specified effect under stated assumptions. Such a calculation is not an observed result and does not show the probability that this completed study detected an effect. The record does not report a trial-specific sample-size rationale or enough information to connect the planning illustration to a prespecified primary analysis. Any participant counts generated under the illustration should be treated as planning quantities, not as evidence about the study's observed outcomes or power.

Why do missing statistical details matter?

Statistical interpretation depends on the analysis plan, endpoint definitions, missing-data handling and analysis population. The registry record reports no analyses and does not describe these details. It is therefore not possible to determine whether the posted safety entries include all enrolled participants, whether participants had different follow-up durations, or how incomplete assessments were handled. These are general sources of uncertainty, not claims that any particular problem occurred in this study.

Likewise, no interim analysis plan, multiplicity procedure, or adjustment method is reported in the registry record. In general, testing multiple outcomes or making repeated decisions can affect the interpretation of statistical evidence, but the appropriate response depends on the prespecified analysis. With no analysis details or primary outcome result reported, statistical significance and comparative effect estimates cannot be assessed. The most defensible reading is limited to the descriptive registry counts and the stated design.

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("GA101+Ibrutinib")
n      <- c(32)
events <- c(32)
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  GA101+Ibrutinib  32  32  100.0  89.1  100.0  89.3  100.0  89.4  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists two outcome measures but reports no analyses. It does not identify a multiplicity strategy, such as a prespecified hierarchy of outcomes or an adjustment for multiple statistical tests. In general, multiplicity matters when several outcomes or comparisons are tested because repeated testing can change the interpretation of statistical evidence. Since no analysis results are reported, there is no basis to evaluate how multiplicity was handled or whether it affected a conclusion.

Missing-data methods and the analysis populations are not reported in the registry record. The record does not say whether all enrolled participants contributed to each endpoint, how incomplete follow-up was treated, or whether any participants were excluded from an analysis. These details are particularly relevant when interpreting counts, because a denominator should correspond to the participants actually assessed for a defined outcome and observation period. The safety entries list 32 participants at risk, but equivalent details for the primary outcome are not reported.

The record also does not describe interim analyses, stopping rules, or the statistical plan used for the reported results. No primary endpoint estimate or analysis population is posted. These omissions do not show that a particular method was or was not used; they mean that the registry record does not report the information needed to assess those methods. The two outcome measures alone are not enough to infer a testing plan, data-completion pattern, or analysis set.

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: sae (9.4%), pneumonia (6.2%), fever/sepsis (irr) (3.1%).

The registry record lists 3 participants with serious adverse events among 32 at risk, 32 participants with other adverse events among 32 at risk, and 0 deaths. The listed serious adverse event terms are SAE (9.4%), pneumonia (6.2%), and fever/sepsis (IRR) (3.1%). These entries describe reported safety findings in the single treated group; they do not compare the combination with another treatment.

The term percentages should not be interpreted as mutually exclusive participant categories. The registry record does not clarify whether one participant could contribute to more than one term, nor does it provide event-level counts alongside each term. It also does not report severity grades, timing, duration, treatment attribution, or whether the events led to treatment interruption or discontinuation. Thus, the figures do not establish a complete clinical profile of the events.

In general, an adverse event is an event recorded during a study, while attribution asks whether it is considered related to treatment. The registry entries do not provide enough detail to determine attribution. Counts also do not account for differences in exposure or follow-up time. The posted information supports a descriptive statement about the recorded counts and terms, not a causal conclusion about the combination.

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

The record establishes that a completed, single-group study enrolled 32 participants with previously untreated CLL in a study of ibrutinib with GA101 (obinutuzumab). It reports safety counts for participants in that group, including 3 participants with serious adverse events among 32 at risk, 32 with other adverse events among 32 at risk, and 0 deaths. It also lists three serious adverse event terms with their registry percentages. These are descriptive findings from the registry record.

The record does not report the primary outcome result. Its title refers to safety, tolerability and DLT, whereas its description refers to remission after discontinuation of ibrutinib. The listed timeframe is 4 weeks. Because the operational definition and result are not reported, the record cannot establish the frequency of DLT or the remission outcome described. The safety counts do not fill that gap.

The study's single-group design does not provide a concurrent treatment comparison. The posted counts therefore do not show whether outcomes were better or worse than they would have been with another approach. They also do not establish that an event was caused by treatment. A causal or comparative interpretation would require evidence and analysis beyond the registry information.

In general, a result may be statistically uncertain even when a count is available, and a precise estimate would not by itself eliminate design limitations or ambiguity in outcome definitions. No interval estimates or analysis results are reported for the primary endpoint. Accordingly, the information supports a bounded description of the enrolled group and reported safety entries, but not a conclusion about comparative efficacy, DLT frequency, or the causal safety profile of the combination.

14. Why This Trial Matters Statistically

This trial is statistically notable because its registry record combines a single-group design with an outcome description that is not fully consistent with the primary outcome title. The title emphasizes safety, tolerability and dose-limiting toxicity, while the description specifies remission after discontinuation of ibrutinib. A clearly defined endpoint is essential for interpreting what a count represents. Without a reported operational definition and result, the primary question cannot be answered from the posted record.

The study also illustrates the distinction between describing outcomes and estimating a comparative treatment effect. A single-group record can document counts among participants who received an intervention, but it lacks a concurrent comparison group for separating treatment effects from other influences. This distinction remains important even when the study is completed and the enrolled group is clearly identified.

The safety entries show why denominators, event definitions and follow-up details matter. The registry reports participant counts and selected serious event terms, but does not provide event-level detail, exposure-adjusted rates, precision estimates, or treatment attribution. Those omissions constrain the questions that can be addressed statistically. Counts are useful descriptive information, but they do not by themselves resolve uncertainty about timing, overlap among event terms, or causality.

Finally, the planning assumptions describe a two-arm illustration, while the registered study design is single group. Recognizing this distinction prevents a planning calculation from being mistaken for the trial's actual design or an observed-power result. Taken together, these features make the record a useful example of how design, outcome specification and reporting determine the scope of statistical interpretation.

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.

Several limitations specific to this record restrict interpretation. The primary outcome title and description refer to different concepts: safety, tolerability and DLT in the title, and remission after discontinuation of ibrutinib in the description. Although a 4 weeks timeframe is listed, the record does not explain how the outcome was defined, assessed, or connected to that timeframe. The primary outcome result is not reported.

The study is listed as single group, with no masking and no allocation to a comparator. This prevents a randomized within-study comparison. The record lists 32 enrolled participants, but does not report how many contributed to each primary endpoint analysis or whether follow-up differed across participants. Missing-data handling and analysis populations are not reported in the registry record.

The safety entries are limited to counts and selected serious event terms. The registry record does not provide detailed event counts for each term, severity grading, timing, duration, attribution, or exposure-adjusted rates. The relationship between the listed terms and the overall serious adverse event count is not clarified. No precision estimates for the safety results are reported.

The record lists two outcome measures and no analyses. It does not report a statistical analysis plan, multiplicity approach, interim analyses, or a trial-specific sample-size justification. The described planning illustration assumes two arms and equal allocation, which does not match the recorded single-group design. These reporting limitations mean that the posted results cannot support a detailed assessment of the primary outcome or a comparative treatment effect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients. — NCT02315768.
• Registry record last updated 2025-09-15; status last verified 2025-08.
• Results first posted 2025-09-15.
• 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

The registry record describes a completed phase Ib/II, single-group study of ibrutinib with GA101 (obinutuzumab) in previously untreated CLL. The intended population was people over 65 years of age or with comorbidities that precluded chemotherapy-based treatment. Enrollment was 32. The study lists no masking and no separate comparator group.

The primary outcome title concerns safety, tolerability and DLT, while its description refers to remission after discontinuation of ibrutinib; the listed timeframe is 4 weeks. The primary result and the analyses are not reported in the registry record. Safety entries include 3 participants with serious adverse events among 32 at risk, 32 with other adverse events among 32 at risk, and 0 deaths, along with three listed serious event terms. These data are descriptive and do not provide a randomized comparison or establish causality.