A Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) (NCT03474679), a na phase 3 study. The primary outcome is Overall Response Rate (ORR).

2. Clinical Question

These features frame what can be learned. The study describes outcomes among participants who received ibrutinib, but its design does not separate treatment-related changes from the course of cGVHD, other care, or differences among participants. The response definition is clinically structured around changes across organs or sites, rather than a single symptom or laboratory measurement. However, without a posted response estimate and an account of its uncertainty, the registry record does not establish how often participants met that definition or how precisely the rate was estimated.

3. Trial Design

This was a Phase 3, single-group study sponsored by Janssen Pharmaceutical K.K. The registry lists 19 enrolled participants and a completed status. The study began on 2018-05-01, with primary completion recorded as 2021-11-29. Those dates describe the registered study timeline; they do not supply an outcome estimate or explain why the study ended when it did.

Participants received ibrutinib at 420 milligram (mg) orally once daily, starting on Week 1 Day 1. The treatment description allows discontinuation in the event of intervening unacceptable toxicity or when other participant discontinuation criteria were met. The registry record does not report additional details about how long each participant remained on treatment or the treatment exposure actually received.

Allocation is listed as not applicable, masking as none, and the model as single-group. Thus, the design has no concurrent control arm and no random assignment between study treatments. The findings can describe outcomes observed in the treated group, but cannot by themselves determine how outcomes would have differed under another treatment or under no study treatment. In particular, there is no like-for-like control comparison in this study.

The primary endpoint was overall response rate (ORR), expressed as the percentage of participants with a complete or partial response under NIH criteria. The assessment timeframe was up to 3 year 6 months. Other registered outcomes include sustained response, duration of response, response at individual timepoints, corticosteroid use over time, symptom-scale improvement, treatment-emergent adverse events, and pharmacokinetic measures of ibrutinib.

The registry lists 23 outcome measures, but does not report an analysis count for the posted results. Details of the protocol’s sample-size justification, planned interim analyses, and full statistical analysis plan are not reported in the registry record. The distinction matters: a study’s phase and registered endpoint identify its intended evaluation, but do not reveal the assumptions behind its design or the methods ultimately used for analysis.

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: All treated analysis set included all enrolled participants who received at least 1 dose of 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.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate (ORR), measured over Up to 3 year 6 months.

The primary endpoint is the overall response rate (ORR), defined as the percentage of participants who achieved complete response (CR) or partial response (PR), without new cGVHD therapy and without progression of the underlying disease or death. Assessment is based on the National Institutes of Health Consensus Development Project Criteria (2014), with a timeframe of up to 3 year 6 months.

Under the registered definitions, CR means resolution of all manifestations in each organ or site. PR means improvement in at least one organ or site without progression in any other organ or site. Progression means clinically meaningful worsening in one or more organs, regardless of improvement elsewhere. These rules combine evidence across affected organs rather than treating improvement in one location as sufficient if another location worsens.

A percentage is used because the endpoint asks what proportion of the treated analysis population met the response definition. This can make a complex clinical response easier to summarize, but it also reduces varied response patterns to a binary classification: each participant either meets the endpoint definition or does not. The registry record defines the endpoint and identifies the treated analysis population as enrolled participants who received at least one dose of study drug.

The endpoint is useful for describing response under the specified criteria and follow-up window. It does not, on its own, establish that ibrutinib caused a response, because the design has no concurrent comparator. The observed ORR, its denominator, and an estimate of statistical uncertainty are not reported in the registry record. Consequently, the endpoint’s definition is available, but its observed value and precision cannot be assessed from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registered primary measure is a binary participant outcome summarized as a percentage: a participant either meets the response definition or does not. ORR combines complete and partial responses under the NIH Consensus Development Project Criteria (2014). The criteria describe complete response as resolution of all manifestations in each organ or site, and partial response as improvement in at least one organ or site without progression elsewhere. The definition also excludes response in the presence of new cGVHD therapy, underlying disease progression, or death.

What does a percentage measure?

A percentage summarizes the share of an analysis population that meets a specified event definition. For this study, the registered treated analysis population includes all enrolled participants who received at least one dose of study drug. In general, the interpretation of a percentage depends on both the number meeting the definition and the denominator used. A denominator must be clearly tied to an analysis population and assessment rule, especially when some participants have missing or unevaluable assessments.

The registry record does not report the observed ORR, its numerator, or the denominator used for the posted primary result. It also does not report a confidence interval or another measure of uncertainty for ORR. Without those items, readers cannot assess the observed response frequency or its statistical precision. The registered population definition helps describe who was intended to contribute, but it does not substitute for the actual analysis details.

Why does uncertainty matter?

General statistical explanation: an estimate from a sample is subject to sampling variability. A confidence interval gives a range of values compatible with the observed data under the method’s assumptions. It is not a guarantee that the true value lies in that particular interval, and it does not address every source of bias, such as outcome misclassification or lack of a control group. Here, because no primary estimate or interval is reported, statistical precision cannot be evaluated from the registry record.

The study enrolled 19 participants. General principle: when a percentage is based on a small group, changing the classification of one participant can noticeably change the percentage. This makes transparent reporting of the numerator, denominator, and uncertainty especially useful. It does not justify creating an estimate when the registry does not report the underlying response count.

What can a single-group design estimate?

A single-group study can describe the outcomes observed among its participants under the study’s treatment and assessment procedures. It cannot directly estimate a contrast against an untreated or differently treated group. General statistical explanation: causal comparisons require a credible counterfactual, meaning an estimate of what would have happened to comparable participants under a different condition. Randomization and a concurrent control group are common ways to support such comparisons. This study is recorded as single-group, with allocation not applicable and no masking, so it does not provide that kind of concurrent comparison.

Even if a response estimate were posted, interpretation would need to distinguish the observed response proportion from a treatment effect. Participants’ disease course, care beyond the study drug, and other factors could contribute to outcomes. The registry record does not report an adjusted comparison or a control group from which to separate these influences.

What do the planning assumptions mean?

The sample-size material is identified as a planning illustration based on an observed effect, not as the trial’s own design. Its assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. Those assumptions describe a hypothetical planning calculation. They are not evidence that this single-group study enrolled the number of participants required for a two-arm comparison, and they are not observed power.

General statistical explanation: power is a design quantity calculated under specified assumptions about an effect, variability, sample size, and testing procedure. It is not a measure of whether a completed study’s finding is true. A retrospective calculation based on an observed effect can be especially difficult to interpret because the observed effect is itself uncertain. No trial-specific sample-size justification is reported in the registry record, and the planning assumptions should not be treated as a description of the study’s actual design.

How should multiple outcomes be considered?

The registry lists 23 outcome measures, including response over time, duration and sustainability of response, corticosteroid use, symptom-scale change, adverse events, and pharmacokinetic measures. Testing or examining multiple outcomes can raise multiplicity concerns: when many hypotheses are assessed, the chance of at least one apparently unusual finding can increase if no adjustment or hierarchy is used. General statistical principle: interpretation depends on which outcomes were prespecified, which analyses were conducted, and whether any multiplicity procedure was applied. The registry record does not report those details or a multiplicity adjustment.

The posted record also does not provide the primary efficacy estimate or a detailed account of missing-outcome handling, censoring rules for time-to-event outcomes, or the analysis methods used for secondary outcomes. Those omissions restrict independent assessment of how the registered endpoint was analyzed. The endpoint definition and the planned timeframe are clear, but the analytical implementation and numerical efficacy findings are 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("Ibrutinib 420 mg")
n      <- c(19)
events <- c(16)
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  Ibrutinib 420 mg  19  16  84.2  60.4  96.6  62.4  94.5  62.1  94.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 23 outcome measures, including the primary ORR and several secondary measures related to response over time, duration of response, corticosteroid use, symptoms, adverse events, and pharmacokinetics. Multiple outcomes can create multiplicity concerns when many hypotheses are assessed. General statistical principle: if several statistical tests are performed, the chance of at least one apparently significant result can rise unless the testing strategy accounts for the number and relationship of the tests. The registry record does not report a testing hierarchy, adjustment method, or other multiplicity strategy.

The record identifies the primary analysis population as all enrolled participants who received at least one dose of study drug. It does not report the number included in the primary endpoint analysis or the observed response numerator and denominator. It also does not describe how missing response assessments, incomplete follow-up, or participants who discontinued treatment were handled. Those details matter because different missing-data rules can produce different analysis populations and estimates.

For secondary outcomes such as duration of response and change over time, specific analysis populations, censoring rules, and missing-data methods are not reported in the registry record. The registry lists no analyses in its posted analysis information. This means the registered outcome definitions can be read, but the numerical results and the methods used to produce them cannot be independently evaluated from the record.

The registry record also does not report interim analyses or the protocol’s sample-size justification. Their absence from the record should not be interpreted as proof that they did or did not occur; the details are not reported in the registry record. The primary response result itself is also not reported, limiting any assessment of multiplicity’s practical effect on the efficacy findings.

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: pneumonia (36.8%), cellulitis (15.8%), renal impairment (10.5%), immune thrombocytopenia (5.3%), atrial flutter (5.3%).

The posted safety figures list 19 participants at risk for serious adverse events, with 12 affected; for other adverse events, 19 were at risk and 19 were affected. The record also lists 7 deaths. These are counts from the treated group, not comparisons against another group. They do not establish that ibrutinib caused the events or deaths.

The listed serious adverse-event terms and percentages are pneumonia (36.8%), cellulitis (15.8%), renal impairment (10.5%), immune thrombocytopenia (5.3%), atrial flutter (5.3%), and cataract (5.3%). These terms describe the serious events recorded; the registry information does not specify whether participants could contribute more than one term, so the percentages should not be added or treated as mutually exclusive categories. The record does not provide enough detail to infer event timing, duration, severity beyond the serious classification, or treatment relatedness for each event.

Safety counts are descriptive. In a single-group study, there is no concurrent comparison of event frequency under another treatment or no study treatment. The figures therefore characterize events reported among participants in this study; they do not provide a comparative estimate of excess risk.

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

The registry record establishes that a Phase 3, single-group study evaluated daily oral ibrutinib in Japanese participants with steroid-dependent or steroid-refractory cGVHD. It defines ORR using complete and partial response under NIH criteria and specifies a follow-up timeframe of up to 3 year 6 months. These details explain the clinical question the study was designed to address.

The record does not report the observed ORR. It therefore does not show what proportion of the treated analysis population met the primary response definition. Nor does it provide an uncertainty interval or another statistical measure that would show the precision of an ORR estimate. The study’s endpoint definition is not itself evidence that responses occurred at any particular rate.

The design also does not support a direct causal comparison. With no comparator arm and no random allocation, the study cannot show how the same population would have fared under another treatment or without study treatment. Any outcomes observed in the treated group could reflect several influences. In general, a single-group result is descriptive unless supported by an appropriate comparison and analysis.

The safety information reports serious adverse events in 12 of 19 participants, other adverse events in 19 of 19 participants, and 7 deaths. It also lists selected serious-event terms and percentages. These data warrant careful description, but the registry information does not establish that the study drug caused any specific event. Nor can the counts alone provide a comparative safety estimate.

Thus, the posted information allows readers to understand the study population, intervention, response definition, and selected safety counts. It does not provide a numerical primary efficacy result, its precision, a control comparison, or the details needed to judge missing-data and multiplicity procedures. Conclusions should remain within those boundaries rather than treating the trial’s objective as a reported finding.

14. Why This Trial Matters Statistically

This trial is statistically notable because it pairs a clearly defined response endpoint with a single-group design and a small enrolled population. The endpoint specifies what constitutes complete or partial response across organs or sites, and it excludes response accompanied by new cGVHD therapy, disease progression, or death. Such explicit criteria help make the intended outcome interpretable and distinguish response from a general impression of improvement.

At the same time, a precisely defined endpoint does not resolve limitations in comparison or reporting. With no control arm, the design cannot isolate an effect attributable to ibrutinib from other influences on outcomes. With 19 participants, the size of the group also makes transparent reporting of response counts and uncertainty especially important. The registry record does not report the primary ORR estimate or its uncertainty, so readers cannot assess the actual response frequency or its precision.

The record’s distinction between a defined analysis population and the absence of posted analysis details is also important. It identifies enrolled participants who received at least one dose as the intended treated set, while the observed endpoint count, denominator, missing-data handling, and statistical analysis details are not reported. Those elements are necessary to understand how the result was derived.

Finally, the listed safety counts are descriptive rather than comparative. The serious-event terms and death count provide information about events recorded in the group, but do not establish causation or quantify relative risk. The statistical value of the record lies in clarifying the study’s design, endpoint, and reporting limits; it does not permit a quantitative conclusion about primary efficacy.

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 most consequential limitation for interpreting efficacy is that the registry record does not report the primary ORR result. Although the response criteria, analysis population definition, and assessment timeframe are registered, the response count, analysis denominator, and uncertainty estimate are unavailable. The efficacy question therefore cannot be answered quantitatively from the posted information.

The single-group design has no concurrent comparator and no random allocation. Consequently, it cannot directly distinguish treatment-associated outcomes from the underlying course of cGVHD or other influences. Lack of masking is also recorded. The registry does not provide details that would allow assessment of how outcome assessments were conducted in practice or whether safeguards against assessment bias were used.

Enrollment was 19 participants, and the study population is described as Japanese participants with steroid-dependent or steroid-refractory cGVHD. The size and described population limit how far the findings, if fully reported, could be generalized. The record does not report additional participant characteristics or subgroup results that would clarify the range of clinical circumstances represented.

Methods needed to assess the analysis are not reported, including the handling of missing outcome data, the statistical analysis plan, any multiplicity strategy, interim analyses, and the trial’s sample-size justification. The safety summary gives counts and selected serious-event terms but does not provide event-level timing or treatment relatedness in the information available. The registry also does not provide comparative safety data. These limitations mean the posted record supports a study-design description and a limited safety summary, but not a complete evaluation of efficacy, precision, or causality.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) — NCT03474679.
• Registry record last updated 2025-02-04; status last verified 2025-01.
• Results first posted 2023-02-03.
• 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 completed Phase 3 study enrolled 19 Japanese participants with steroid-dependent or steroid-refractory cGVHD. It used a single-group, unmasked design with no comparator arm. Participants received oral ibrutinib at 420 milligram (mg) once daily, beginning on Week 1 Day 1.

The primary endpoint was ORR, defined using NIH Consensus Development Project Criteria (2014), over a timeframe of up to 3 year 6 months. The registry record does not report the observed primary response rate, its analysis denominator, or an uncertainty estimate. It lists 23 outcome measures but does not report a posted analysis count.

Safety information lists serious adverse events in 12 of 19 participants, other adverse events in 19 of 19 participants, and 7 deaths. These figures are descriptive and do not establish treatment causation or provide a comparison with another group.