Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (NCT04624633), a non-randomized phase 2 study. The primary outcome is Complete Remission (CR) Rate After 24 Cycles.

2. Clinical Question

The study asks whether participants with chronic lymphocytic leukemia (CLL) achieve complete remission after treatment with acalabrutinib, umbralisib, and ublituximab. It includes separate cohorts for relapsed disease and previously untreated disease. The registry describes acalabrutinib and umbralisib starting at C1D1, with ublituximab starting at C7D1, and treatment continuing for a maximum of 24 cycles.

The registry also lists partial remission rate after 24 cycles and median progression-free survival as secondary outcomes. Their results are not reported in the registry record. Consequently, the record describes the questions the study was designed to assess, but does not provide outcome estimates with which to answer them.

3. Trial Design

This is a phase 2, non-randomized, unmasked, parallel study. The registry lists an enrollment of 29 and describes two cohorts: participants with relapsed disease and participants with previously untreated disease. Because assignment was not randomized and the cohorts represent different disease histories, their outcomes should not be treated as if they came from comparable treatment and control groups.

Both cohorts are described as receiving the same drug combination on the same stated schedule: acalabrutinib and umbralisib beginning at C1D1, followed by ublituximab beginning at C7D1. Treatment could continue for a maximum of 24 cycles, with post-treatment follow-up for a maximum of 5 years. The registry gives an overall median number of cycles of 24, with a range of 1-25. This overall treatment description does not establish how many participants completed the treatment period required for the primary endpoint.

The primary endpoint is the complete-remission rate after 24 cycles, defined as the proportion of participants achieving complete remission according to the 2018 IW-CLL criteria. The endpoint population is described as patients who completed 24 cycles of treatment. The number included in that population, the observed remission proportion, and its 95% confidence interval are not reported in the registry record.

The study started on 2020-12-15, and the listed primary completion date is 2023-12-21. Its status is active, not recruiting. The registry lists Jennifer R. Brown, MD, PhD, as sponsor. No randomized comparator is described, so comparisons between the cohorts can describe their separate observed outcomes if reported, but cannot isolate a treatment effect by contrasting one cohort with an equivalent untreated or alternative-treatment group.

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: Patients who completed 24 cycle of treatment.

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 Remission (CR) Rate After 24 Cycles, measured over According to this endpoint is after 24 cycles. Overall median number of cycles is 24 with range 1-25..

The primary endpoint is the complete-remission rate after 24 cycles. It is defined as the proportion of participants achieving complete remission according to the 2018 IW-CLL criteria. A proportion expresses how often a specified outcome occurs within a defined population. The registry identifies the endpoint population as patients who completed 24 cycles of treatment.

A remission endpoint can describe the observed response status at the stated assessment point. It differs from a time-to-event outcome, which concerns how long participants remain free of an event or how long it takes for an event to occur. The registry lists median progression-free survival as a secondary outcome, but does not report its result. Partial remission rate after 24 cycles is also listed as a secondary outcome.

The registry specifies a 95% confidence interval as the measure of uncertainty for the primary proportion. In general, a confidence interval communicates the precision of an estimate: a less precise estimate has a wider interval, and a more precise estimate has a narrower interval. The observed complete-remission proportion and interval are not reported in the registry record. The endpoint denominator is also not reported, so the primary result cannot be reconstructed from the enrollment figure or the treatment-cycle summary.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical details reported in the registry are limited. The primary outcome is a binary proportion: each participant in the stated endpoint population either meets the complete-remission definition or does not. The measure is the proportion achieving complete remission under the 2018 IW-CLL criteria after 24 cycles. The registry specifies a 95% confidence interval for this proportion, but the observed estimate and interval are not reported in the registry record.

What does a confidence interval convey?

In general, a confidence interval describes uncertainty around an estimate. It is not a guarantee that the true value lies within a particular interval, nor does it describe the range of individual participant outcomes. Its width reflects the precision of the estimate under the method used. For a proportion, the amount of information depends in part on how many participants contribute to the endpoint and how the outcomes are distributed. The endpoint denominator and confidence interval method are not reported in the registry record, so the precision cannot be independently assessed.

Why does the endpoint population matter?

The registry defines the primary population as patients who completed 24 cycles of treatment. That is narrower than the overall enrollment population unless every enrolled participant meets the completion criterion, which the record does not establish. The overall median number of cycles is 24, with a range of 1-25, but this summary does not state how many participants completed 24 cycles or how participants without that assessment were handled. The primary outcome denominator and missing-outcome approach are not reported in the registry record.

What can a non-randomized design establish?

Random allocation is not used. The study instead has parallel cohorts for relapsed disease and previously untreated disease. In general, randomization helps balance measured and unmeasured prognostic characteristics between treatment groups. Without it, differences between cohorts may reflect their distinct clinical populations as well as other factors. These cohorts are not a like-for-like control comparison, and the registry does not describe an adjusted comparison that would support a causal interpretation.

The study is unmasked, meaning masking is listed as none. In general, awareness of treatment or cohort can affect reporting, assessment, and other aspects of a study, although the extent depends on the outcome and its assessment process. The registry identifies the remission criteria but does not report additional information about masked outcome assessment.

How should the secondary outcomes be understood?

Partial remission rate is another proportion, while median progression-free survival is a time-to-event summary. In general, time-to-event analyses account for the timing of events and may also need to address participants whose follow-up ends before an event is observed. The registry lists median progression-free survival but does not report its estimate, the event definition details, follow-up summaries, censoring approach, or analysis method. These details are not reported in the registry record.

What do the analysis entries say?

The registry lists no analysis entries. It does not report a statistical analysis plan, a model for the primary outcome, covariate adjustment, interim analyses, or a sample-size justification. Those details should not be inferred from the endpoint definition or from the presence of a confidence interval field.

The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the target effect is expressed as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power. Their assumptions do not constitute evidence that the trial used those methods for its design or analysis. In general, power is a planning concept tied to assumptions about a future study and a target effect; it is not a measure of how likely a completed study's result is to be correct. No numerical planning estimates or observed primary effect are reported in the registry record.

For count outcomes, over-dispersion is a general concern when variability exceeds what a simple probability model expects. It can make uncertainty estimates too narrow if the analysis assumes less variability than the data contain. The registry record does not describe an over-dispersion analysis, nor does it provide data needed to assess whether this issue applies to the reported outcomes.

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("Cohort 1 - Relapsed Disease", "Cohort 2 - Treatment Naive")
n      <- c(6, 14)
events <- c(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  Cohort 1 - Relapsed Disease  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort 2 - Treatment Naive  14  0  0.0  0.0  23.2  0.0  21.5  0.2  21.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and two secondary outcomes: complete-remission rate after 24 cycles, partial-remission rate after 24 cycles, and median progression-free survival. When a study evaluates multiple outcomes, testing each one can increase the chance of a false-positive finding if each is judged using an unadjusted threshold. In general, a statistical plan may identify a primary outcome, set a testing hierarchy, or adjust for multiple comparisons. The registry record does not report whether any such multiplicity strategy was planned or used.

No outcome analyses are listed in the record. It does not provide the primary estimate, confidence interval, secondary outcome estimates, p-values, or an analysis plan. It is therefore not possible to determine how outcomes were tested, whether results were adjusted for multiple testing, or whether any planned analyses differed from those ultimately conducted. The registry also does not report interim analyses.

The primary endpoint population is described as patients who completed 24 cycles, but the record does not give its size or explain how participants who did not complete 24 cycles were handled. The number of missing primary outcome assessments and the missing-data method are not reported in the registry record. In general, analyses that exclude participants without an endpoint assessment may describe a selected subset if completion is related to prognosis or outcome. That possibility cannot be assessed without information about participant flow, endpoint availability, and the analysis population.

Although the registry reports overall enrollment and an overall treatment-cycle summary, neither identifies the denominator used for the primary endpoint. No assumption about missing outcomes, intention-to-treat analysis, or per-protocol analysis can be made from the information reported.

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: neutrophil count decreased (62.5%), alanine aminotransferase increased (23.8%), aspartate aminotransferase increased (19.0%), diarrhea (14.3%), anemia (12.5%).

The registry reports serious adverse-event information separately for the relapsed-disease cohort and the treatment-naive cohort. It lists 7 affected participants among 8 at risk in the relapsed-disease cohort and 16 affected among 21 at risk in the treatment-naive cohort. It also reports 1 death in the relapsed-disease cohort and 0 in the treatment-naive cohort. These are descriptive counts, not a randomized comparison of safety between treatment and control groups.

The listed serious adverse-event terms and percentages are neutrophil count decreased, 62.5%; alanine aminotransferase increased, 23.8%; aspartate aminotransferase increased, 19.0%; diarrhea, 14.3%; anemia, 12.5%; and abdominal pain, 12.5%. The record does not specify in this information which cohort denominators apply to each listed percentage. These percentages should therefore be read as the registry's reported figures, not recalculated or assigned to a cohort.

In general, an adverse event is an observed medical occurrence, and its appearance in a safety listing does not by itself show that treatment caused it. The registry information does not establish causality or provide a comparative safety analysis. Counts also depend on the participants assessed and the recording rules; further details about those rules are not reported in the registry record.

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

The registry record establishes that a phase 2 study evaluated a three-drug regimen in cohorts with relapsed and previously untreated CLL. It specifies complete-remission rate after 24 cycles as the primary endpoint, defines remission using the 2018 IW-CLL criteria, and identifies the population as patients who completed 24 cycles. It also lists partial remission rate and median progression-free survival as secondary outcomes and reports selected safety information.

The record does not report the observed primary endpoint result, its 95% confidence interval, or the secondary outcome results. It therefore does not show how often complete remission occurred in the defined population or how precisely that proportion was estimated. The overall enrollment and cycle summary do not substitute for an endpoint denominator or outcome estimate.

The study is non-randomized and has no like-for-like control group. Its cohort structure cannot establish what outcomes would have occurred under a different treatment or without the study regimen. Differences between the relapsed and previously untreated cohorts should not be interpreted as treatment effects, because the cohorts have different disease histories and were not randomly assigned.

The safety counts and listed adverse-event percentages describe events recorded in the registry, but do not by themselves show that the regimen caused those events. The record does not provide a randomized safety contrast or further causal analysis.

Accordingly, the registry description supports a careful account of the study design and of which outcomes were intended for assessment. It does not support a conclusion about the magnitude, precision, or comparative effect of the primary or secondary efficacy outcomes. Absence of a result in the registry record is not evidence that an outcome was absent; it means that the result is not reported there.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of why design and endpoint definitions matter when interpreting clinical research. It distinguishes relapsed disease from previously untreated disease, uses a non-randomized parallel design, and defines its primary outcome in a population that completed 24 cycles of treatment. Those features determine what the endpoint can describe and which comparisons it can support.

A response proportion and a time-to-event outcome answer different questions. Complete-remission rate concerns the proportion meeting a remission definition at the specified assessment point. Progression-free survival concerns time to an event and requires methods that account for follow-up and censoring. The registry lists both types of outcomes, but does not report their estimates or analysis details. Readers therefore cannot assess their magnitude or precision from this record.

The difference between overall enrollment and the stated primary endpoint population is also important. Enrollment does not reveal how many participants completed the required treatment period or contributed an endpoint assessment. Without that denominator and information about missing outcomes, the precision and representativeness of a remission estimate cannot be evaluated.

Finally, the absence of randomization limits comparative interpretation. Separate cohort results, if reported, would describe those cohorts but would not provide a controlled estimate of treatment effect. Statistical interpretation depends not only on a numerical result but also on who was analyzed, how outcomes were measured, and what comparison the design can sustain. In this case, key outcome and analysis details are not reported in the registry record.

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 registry record does not report the primary complete-remission proportion or its 95% confidence interval. It also does not report the outcome estimates for partial remission or progression-free survival. This prevents assessment of the observed efficacy outcomes and their precision.

The primary endpoint applies to patients who completed 24 cycles, but the number in that population is not reported. The overall enrollment of 29 and the overall median number of cycles of 24, with a range of 1-25, do not identify the primary analysis denominator. Participant flow, endpoint completeness, and handling of participants who did not complete 24 cycles are not reported in the registry record.

The non-randomized design and separate disease-history cohorts limit comparative interpretation. The study has no like-for-like control comparison, and the record does not report an adjusted analysis that could address differences between cohorts. Masking is listed as none, and further details on outcome assessment procedures are not reported.

The registry lists no analysis entries. A statistical analysis plan, sample-size justification, interim analysis details, outcome models, multiplicity strategy, and missing-data methods are not reported in the registry record. The listed safety information includes affected counts, deaths, and adverse-event percentages, but does not provide enough information to establish causality or interpret the percentages by cohort. These limits mean that the record supports descriptive reporting of the design and selected safety figures, but not a full appraisal of efficacy analysis or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL — NCT04624633.
• Registry record last updated 2026-02-25; status last verified 2026-02.
• Results first posted 2025-02-27.
• 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

This is a phase 2, non-randomized, unmasked, parallel study of acalabrutinib, umbralisib, and ublituximab in relapsed and previously untreated CLL. The registry lists enrollment of 29, a start date of 2020-12-15, a primary completion date of 2023-12-21, and status active, not recruiting. Treatment is described as acalabrutinib and umbralisib starting at C1D1, with ublituximab starting at C7D1; treatment could continue for a maximum of 24 cycles.

The primary endpoint is complete-remission rate after 24 cycles according to the 2018 IW-CLL criteria, in patients who completed 24 cycles. Partial remission rate and median progression-free survival are secondary outcomes. Their results, including the primary estimate and confidence interval, are not reported in the registry record. Selected serious adverse-event counts, deaths, and event percentages are listed, but do not constitute a randomized safety comparison.