Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma (NCT01849263), a na phase 2 study. The primary outcome is Overall Response Rate.

2. Clinical Question

This is a phase II evaluation in a population with relapsed or refractory disease, rather than a comparison designed to estimate the relative effect of ibrutinib against another treatment. The clinical question is whether an objective response was observed during treatment and how precisely the response proportion could be estimated. The record lists overall response rate as the primary outcome, with a timeframe of up to 5 years.

The intended response definition combines complete response and partial response. Complete response requires disappearance of all evidence of disease. Partial response requires at least 50% decrease in the sum of the products of dimensions of up to 6 largest dominant masses, with the other specified criteria concerning nodes and liver or spleen. The registry record does not provide the number of patients meeting either response category. It therefore does not permit a numerical answer to the primary question.

3. Trial Design

This is a phase II, single-group trial of single-agent ibrutinib in relapsed or refractory follicular lymphoma. The registry record lists an enrollment of 41 and identifies the study as non-randomized, with no masking. Because there is no concurrent comparator group, the design can describe outcomes observed among treated participants but cannot by itself isolate a treatment effect from other explanations for those outcomes.

The treatment description specifies ibrutinib by mouth once daily on days 1–28, with courses repeating every 28 days while there was no disease progression or unacceptable toxicity. Patients with progressive disease at the end of course 2 could continue therapy until the end of course 5 at the treating physician’s discretion. This flexibility means treatment exposure could differ according to clinical course and physician judgment; the registry record does not report how often this option was used.

The primary outcome is overall response rate, defined as partial or complete response at any time during treatment. The stated timeframe is up to 5 years. The record says that all patients who began protocol treatment were included in the primary-outcome analysis, but it does not report how many began treatment or how many contributed an evaluable response assessment. Those details are needed to understand the analysis denominator.

Secondary outcomes listed are duration of response, overall survival, progression-free survival, time to response, time to subsequent treatment, and time to treatment failure. The registry record also lists laboratory biomarker analysis. It reports 7 outcome measures and no analysis entries. The details of endpoint definitions, assessment schedules, and statistical models for the secondary outcomes are not reported in the registry record.

The study began on 2013-04-02, and its primary completion date is listed as 2016-06-03. Its status is active, not recruiting. These administrative details describe the registry record, not the completeness of the posted efficacy results. A study can have a recorded completion date while some numerical outcome information remains unavailable in the record.

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: Forty-one patients were enrolled to this study. One patient cancelled prior to beginning protocol treatment and was excluded from all analyses.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All patients that began protocol treatment were included in this analysis.

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: All participants that started protocol treatment are included.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate, measured over Up to 5 years.

Overall response rate is the proportion of participants whose best qualifying objective status during treatment was complete response or partial response. It is a binary endpoint at the participant level: each participant is classified according to whether a response was recorded under the specified criteria. The primary endpoint’s timeframe is up to 5 years, and the record says that the response assessment follows the Revised Response Criteria for Malignant Lymphoma.

Complete response is defined as disappearance of all evidence of disease. Partial response is defined using a reduction of at least 50% in the sum of the products of dimensions of up to 6 largest dominant masses, alongside conditions about other nodes and regression on CT, and no increase in the size of the liver or spleen. Applying prespecified response criteria can make outcome classification more consistent than relying on an informal description of improvement. The registry record does not report the actual response assessments or counts in each category.

In general, a proportion gives an interpretable summary of how often an event—in this case, an objective response—was observed in the analysis population. A confidence interval expresses uncertainty around the estimated proportion: a wider interval indicates less precision, while a narrower interval indicates greater precision. The record states that 95% binomial confidence intervals for the true success proportion will be calculated. It does not report the response proportion or its interval, so neither the observed response frequency nor its precision can be assessed from the registry record.

This endpoint captures whether a response occurred, not how long it lasted. Duration of response is listed separately as a secondary outcome. Overall response rate also does not provide a randomized comparison or, on its own, establish that treatment caused the observed responses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary endpoint such as overall response rate, the basic statistical quantity is the proportion of participants classified as responders among those included in the analysis. A binomial confidence interval is used to express uncertainty around that proportion. In general, the interval reflects the variability expected when a binary outcome is observed in a finite group. It is not a range containing a fixed proportion with certainty, and it does not account automatically for every possible source of bias, such as missing assessments or differences in how participants were selected.

The registry record states that 95% binomial confidence intervals for the true success proportion will be calculated. That method description identifies the intended type of uncertainty interval, but the record does not provide the estimate, interval limits, response count, or analysis denominator. Without those results, it is not possible to check the calculation or comment on the interval’s width. The analysis population is described as all patients who began protocol treatment; the number who began treatment is not reported in the registry record.

Response status is defined using objective response criteria. In general, criteria can reduce ambiguity by specifying which changes count as complete or partial response. The definition in the registry record requires complete disappearance of disease evidence for complete response, and a specified reduction in tumor measurements plus additional conditions for partial response. A participant’s response classification may depend on when assessments were made and how incomplete or unevaluable assessments were handled. The registry record does not report assessment timing, adjudication procedures, or rules for missing response evaluations.

What does a confidence interval contribute?

A point estimate gives a single summary of the observed data, while a confidence interval conveys its statistical uncertainty. If a response proportion were available, the interval could help readers distinguish a precisely estimated proportion from one with considerable uncertainty. It would not establish causality, correct selection bias, or replace a comparison group. The planned 95% interval is mentioned in the registry record, but no interval result is reported there.

Why does the single-group design matter?

In a randomized comparative trial, random allocation is intended to make groups comparable on average, so differences in outcomes can be interpreted in relation to treatment assignment, subject to the trial’s limitations. This trial has one treatment group and no random allocation. Its response outcome can be described, but there is no concurrent control outcome for estimating a relative treatment effect. Comparisons with outcomes from other studies would require care because populations, eligibility, assessment, follow-up, and care may differ; the registry record does not provide a formal external comparison.

The absence of masking is also part of the design description. In general, knowledge of treatment assignment can influence care, reporting, or outcome assessment, especially when an outcome involves judgment. Use of specified response criteria may support consistent classification, but does not eliminate every potential influence. The registry record does not describe blinded outcome review or other safeguards, so those procedures are not reported in the registry record.

What do the planning assumptions mean?

The registry record describes sample-size planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustrations concern a total number of events; for other outcomes, they concern participants per arm. These are planning assumptions, not observed trial results, and they do not describe the single-group study’s actual allocation.

In general, a planning illustration asks how much information a hypothetical study might need under stated assumptions. Equal allocation between two arms is a hypothetical comparative setup and should not be mistaken for the design of this single-group trial. A normal approximation is a method for estimating planning requirements; its suitability depends on the outcome and assumptions. The registry record does not report numerical planning estimates, the observed effect used as a reference, or a protocol-based sample-size justification. The stated illustrations must not be interpreted as observed power, as evidence that the trial had a particular probability of detecting an effect, or as a description of the trial’s actual design.

Over-dispersion is a general concern when observed variability exceeds what a simple statistical model assumes. For binary outcomes, this can arise when participants differ in their underlying chances of response or when outcomes are correlated. A model that ignores extra variability can make uncertainty appear smaller than it is. The registry record identifies a binomial confidence-interval approach for the primary proportion, but does not report an over-dispersion assessment or a model accommodating it. This point is a general statistical consideration, not a claim that over-dispersion occurred in this trial.

The registry record reports no analysis entries. As a result, it does not specify the implemented statistical procedures beyond the planned binomial interval description for the primary outcome and the assumptions attached to planning illustrations. It does not report whether analyses were adjusted, whether outcomes were examined at interim points, or how deviations from planned methods were addressed. Each of those details is not reported in the registry 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("Treatment (Ibrutinib)")
n      <- c(40)
events <- c(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  Treatment (Ibrutinib)  40  0  0.0  0.0  8.8  0.0  8.8  0.1  8.6

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes or repeated statistical tests are considered. In general, the more opportunities there are to identify an apparently notable result, the more important it becomes to explain which outcomes were primary, how secondary analyses were interpreted, and whether any adjustment or hierarchy was planned. The registry record names overall response rate as the primary outcome and lists secondary outcomes of duration of response, overall survival, progression-free survival, time to response, time to subsequent treatment, and time to treatment failure. It does not report a multiplicity adjustment or a testing hierarchy; these are not reported in the registry record.

The record says that all patients who began protocol treatment were included in the primary-outcome analysis. It does not report how many began treatment, how many had response assessments, or how missing or unevaluable assessments were classified. No missing-data strategy is reported in the registry record. These gaps matter because the analysis denominator and the treatment of unavailable outcomes can affect the interpretation of a proportion. The stated enrollment of 41 does not establish the number included in the response analysis.

The registry record does not report interim analyses or stopping rules. It also does not report whether the primary analysis followed a prespecified statistical analysis plan, or whether any analysis population differed from the stated population. The record gives no details about the completeness or duration of follow-up for the secondary outcomes. As a result, readers cannot assess whether missingness, selective reporting, or repeated testing affected the estimates.

These are reporting limitations, not evidence that a particular procedure was or was not used outside the record. For the primary endpoint, the record supplies the intended response definition and confidence-interval method but not the numerical result or denominator. For the secondary endpoints, it lists outcome names without reported estimates in the registry record.

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: diarrhea (5.0%), infections and infestations - other, specify (5.0%), spleen disorder (2.5%), cardiac disorders - other, specify (2.5%), chest pain - cardiac (2.5%).

The treatment-group safety fields list 40 participants at risk for serious adverse events and 10 affected. For other adverse events, the fields list 40 at risk and 40 affected. The registry record also lists 1 death. These are recorded counts, not comparisons with a control group, and they do not establish that an event or death was caused by ibrutinib. The registry record does not report cause-of-death attribution in these figures.

The serious-event terms with listed percentages are diarrhea (5.0%), infections and infestations—other, specify (5.0%), spleen disorder (2.5%), cardiac disorders—other, specify (2.5%), chest pain—cardiac (2.5%), and supraventricular tachycardia (2.5%). These percentages are registry entries for the named terms; the record does not provide additional detail about event severity, duration, timing, recurrence, or participant-level overlap among terms. They should not be added together to estimate the proportion affected.

In general, an adverse-event count describes events recorded during a defined period and within a stated population. Interpretation depends on the event definitions, surveillance, exposure time, and attribution procedures. The registry record does not report those details for these safety entries. Because this is a single-group trial, the figures describe the treatment group and cannot quantify how frequently comparable events would have occurred without the treatment.

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

The registry record establishes that a phase II, single-group study evaluated ibrutinib in relapsed or refractory follicular lymphoma and designated overall response rate as its primary outcome. It also states how complete and partial response were defined and that a 95% binomial confidence interval was planned. These details clarify what the primary outcome was intended to represent.

The record does not report the numerical response result. There is no response count, response proportion, or confidence interval in the record. Therefore, the frequency of objective response and the precision of its estimate cannot be determined from the registry record. The enrollment entry of 41 does not supply a response denominator: the primary analysis population is described as patients who began protocol treatment, and the number who began treatment is not reported.

Even if the response estimate were reported, a single-group study would describe outcomes observed among treated participants, rather than provide a randomized estimate of the difference between ibrutinib and another treatment. A response during treatment is not by itself proof that treatment caused the response. The registry record does not support a comparative claim, and no medical recommendation follows from the available information.

The listed secondary outcomes address different questions. Duration of response concerns how long a response lasts; overall survival, progression-free survival, time to response, time to subsequent treatment, and time to treatment failure concern other aspects of outcome and follow-up. The registry record lists these measures but does not report numerical results for them. Their definitions and analysis details are also not reported in the registry record.

The safety entries provide counts and term-specific percentages for the treatment group, but no control-group comparison. They should be read as descriptive registry data, not as estimates of excess risk or as proof of causal attribution. The death count does not identify whether the death was related to treatment in the reported information.

In short, the registry record supplies the study design, endpoint definition, and some safety entries, but not the primary efficacy estimate or its uncertainty. The absence of a reported numerical efficacy result should not be mistaken for a zero response, nor should it be interpreted as evidence that the intervention did or did not have an effect.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between measuring an outcome and reporting an estimate. The registry record gives a defined primary endpoint—complete or partial response during treatment—and identifies a binomial confidence interval as the intended way to describe uncertainty. Without the observed count and interval, however, the central statistical result is unavailable. A precise endpoint definition is useful, but it cannot answer how often the endpoint occurred.

The study also illustrates what a single-group design can and cannot estimate. It can describe the proportion of treated participants who met response criteria, if that proportion and its denominator are reported. It cannot provide a randomized comparison of outcomes between treatment strategies. This distinction is especially important when interpreting an observed response as evidence about treatment effects: descriptive outcomes and causal comparisons are different statistical questions.

Another useful lesson is that the denominator must match the stated analysis population. Enrollment is recorded as 41, whereas the primary analysis is described as including patients who began protocol treatment. The number who began treatment and the number with evaluable response data are not reported in the registry record. Readers therefore cannot verify which population an estimate would represent even if the result were available.

The registry lists several secondary outcomes and safety entries, which make clear that a trial can address multiple questions. Multiplicity, incomplete outcome reporting, missing assessments, and follow-up all affect interpretation, but the relevant analysis details are not reported in the registry record. The record’s planning assumptions are also described as illustrations using a hypothetical two-arm allocation, distinct from the actual single-group design. Together, these features underscore why study design, analysis population, uncertainty, and reporting completeness should be considered alongside any headline endpoint.

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 principal limitation for interpreting efficacy is that the registry record does not report the primary response count, proportion, or confidence interval. The record therefore does not permit evaluation of the magnitude or precision of the primary endpoint. Although enrollment is listed as 41, the number who began protocol treatment and the response-analysis denominator are not reported in the registry record.

The single-group, non-randomized design has no concurrent control. Any reported response proportion would be descriptive of the treated group and would not estimate a randomized difference against another therapy. The absence of masking is also recorded. The registry record does not describe blinded response assessment, central review, or other procedures that might limit assessment influence.

Important operational details are not reported in the registry record, including response assessment timing, handling of missing or unevaluable assessments, actual treatment exposure, and the frequency with which the option to continue after progression at the end of course 2 was used. The record does not report the statistical analysis plan, interim analyses, stopping rules, or multiplicity procedures. These omissions limit assessment of how the planned methods were implemented and how complete the reported outcomes are.

The registry lists several secondary outcomes but does not report numerical results for them. It also does not give detailed definitions or follow-up information for those outcomes. Safety reporting includes counts and selected term percentages, but the record does not provide participant-level overlap, event timing, exposure-adjusted rates, or attribution details. The safety entries therefore cannot support a comparative risk estimate.

Finally, the planning assumptions describe illustrations based on an observed effect and a hypothetical equal allocation between two arms, whereas the trial is single-group. The numerical planning estimates and the reference effect are not reported in the registry record. These illustrations should not be treated as evidence of the trial’s actual design or its observed statistical power.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma — NCT01849263.
• Registry record last updated 2026-09-11; status last verified 2026-09.
• Results first posted 2018-04-26.
• 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 NCT01849263, a phase II single-group trial of ibrutinib in relapsed or refractory follicular lymphoma. It lists enrollment of 41, no masking, and no comparator group. Treatment was oral ibrutinib once daily on days 1–28, with courses repeating every 28 days subject to disease progression or unacceptable toxicity.

The primary outcome was overall response rate, defined as complete or partial response during treatment, with a stated timeframe of up to 5 years and a planned 95% binomial confidence interval. The record says the analysis included all patients who began protocol treatment. It does not report the response count, proportion, confidence interval, or number who began treatment.

Secondary outcomes include duration of response, overall survival, progression-free survival, time to response, time to subsequent treatment, and time to treatment failure. The registry also lists safety counts and selected serious adverse-event terms. Numerical secondary efficacy results and further analysis details are not reported in the registry record.