Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing (NCT02604511), a na phase 2 study. The primary outcome is Major Response Rate.

2. Clinical Question

This is a question about the frequency of a specified response among participants in the study, not a randomized comparison of treatment effects. The response definition uses a threshold in serum IgM and groups Partial Response and better response categories together. It does not, by itself, answer whether responses lasted, whether symptoms changed, or how outcomes compared with an alternative. Duration of Response is listed as a secondary outcome, but its result is not reported in the registry record. The record describes the study as evaluating safety and efficacy, while the posted primary-outcome information gives the endpoint definition and timeframe rather than an observed result.

3. Trial Design

The registry identifies NCT02604511 as a Phase II study of ibrutinib in people with symptomatic, previously untreated Waldenstrom's Macroglobulinemia. It lists Dana-Farber Cancer Institute as the sponsor, a single-group model, no masking, and allocation as not applicable. The arm description calls the study single arm, open label, and single center. These features mean participants were not assigned to concurrent randomized treatment groups in the design described by the record.

Enrollment is listed as 31. The study status is completed; the recorded start is 2016-01 and primary completion is 2022-11-01. The intervention is ibrutinib. The arm description says treatment was administered in 4-week cycles for up to 48 cycles. The registry lists Duration of Response as a secondary outcome and reports six outcome measures overall.

A single-group Phase II design can describe outcomes observed among participants receiving the intervention, but it does not create a controlled estimate of how those outcomes compare with another treatment. Open-label status also means the study was not masked. The registry record does not report a randomized comparator, a control arm, or an allocation ratio. It does not report a statistical analysis plan or an interim-analysis plan. The number of analyses recorded is 0, and no primary response result or analysis is reported in the registry record. Consequently, the design and endpoint can be described, but the response estimate and its precision cannot be assessed from the registry information.

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 participants except one participant determined to be ineligible

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 Major Response Rate, measured over 4 years.

The primary endpoint is Major Response Rate, expressed in the registry as a count of participants. The endpoint description says it is intended to assess the percentage of participants with a Partial Response (PR), defined as a 50% reduction or more in serum IgM, or a better response. The stated timeframe is 4 years. The primary-outcome population is described as all participants except one participant determined to be ineligible.

This endpoint turns a laboratory change into a response category using a specified threshold. In general, a threshold-based outcome gives a clear rule for classifying whether a participant meets the response definition. It also discards information about the size of changes within each category: participants just meeting the threshold and participants with larger reductions are both included as PR or better. The endpoint is therefore useful for describing the proportion meeting a predefined response criterion, but it is not a complete description of each participant's course or of the duration of response.

The registry record does not report how many participants met the criterion, the resulting percentage, or an uncertainty interval. The definition and timeframe alone do not establish whether the endpoint was met at the group level.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry information supports a limited statistical description. It identifies the study as Phase II, single group, open label, and single center; specifies a binary response outcome; and gives the response rule and timeframe. It does not report the statistical methods used to analyze that endpoint. The explanations below describe general statistical ideas and should not be read as methods confirmed for this study.

What does a binary response outcome represent?

In general, a binary outcome assigns each participant to one of two categories for the analysis, such as meeting or not meeting a prespecified response criterion. A response rate is based on the number meeting the criterion relative to the analysis population. The registry describes the primary endpoint as a count of participants and describes its aim as assessing a percentage. It does not report the number who met the response definition, the number included in the final endpoint analysis, or the calculated percentage. The primary population description excludes one participant determined to be ineligible, but the record does not give a separate response-evaluable denominator.

A count and a rate are related but are not interchangeable. A count states how many participants had the outcome; a rate also requires a denominator. In general, an estimate of the rate is more informative when read together with its denominator and uncertainty interval. Because the response result and its analysis are not reported, neither the point estimate nor its precision can be reviewed from the registry record.

How should uncertainty be understood?

In general, a confidence interval communicates the sampling uncertainty around an estimate, subject to the assumptions of the method used. A narrow interval indicates greater precision than a wide interval, while neither guarantees that the study population represents people outside the trial. For a binary rate, methods for intervals can differ, especially when the number of outcomes or the analysis population is limited. The registry record does not name an interval method or report an interval for major response rate. It is therefore not possible to judge the precision of the intended endpoint estimate.

A p-value, when used, addresses compatibility of data with a specified statistical null model; it is not a measure of clinical importance and does not replace an effect estimate with an interval. No p-value or hypothesis test for the primary endpoint is reported in the registry record. No adjusted analysis or model is reported either. The absence of these details should not be interpreted as evidence that a particular method was used or that a particular hypothesis was tested.

What does the single-group design allow?

In general, a single-group study can estimate outcomes observed among its participants, subject to the endpoint definition, follow-up, and missing-data handling. Without a randomized comparator, it cannot directly estimate a between-group treatment contrast. Open-label status means masking is absent as recorded, and the record does not describe a blinded outcome assessment. These design features matter when interpreting results, but they do not determine the direction or size of an unreported response result.

The study is not described as a randomized comparison, and the registry explicitly characterizes the arms as not being a like-for-like control comparison. The planning assumptions mention equal allocation between two arms and a normal approximation, but those are assumptions for a planning illustration computed from an observed effect, not the design used in this single-group trial. The sample-size illustrations are not observed power and should not be read as evidence about the trial's achieved ability to detect an effect. The registry record does not provide a trial-specific sample-size justification.

Why do analysis populations matter?

An analysis population defines which participants contribute to an endpoint estimate. In general, changing eligibility or evaluability rules can change both the numerator and denominator of a response rate. The primary-outcome description says the population includes all participants except one participant determined to be ineligible. It does not provide the final denominator, explain how missing response assessments were handled, or identify an analysis population by a named convention. Those details are not reported in the registry record, so the endpoint population cannot be reconstructed beyond the description given.

The safety record uses separate at-risk and affected counts for serious and other adverse events. Those counts describe the registry's safety reporting and should not be treated as the denominator or numerator for the primary efficacy endpoint. Safety and efficacy outcomes answer distinct questions and may use different definitions or populations.

What methods remain unknown?

The number of analyses recorded is 0. The registry record does not report an inferential test, a confidence-interval method, a model, covariate adjustment, handling of repeated assessments, missing-data imputation, or interim analyses. It does not report whether the primary endpoint was assessed at a fixed visit or how response confirmation was handled. These are not details that can be inferred from the endpoint wording. In general, transparent reporting of the analysis population, denominator, missingness, estimate, and uncertainty is necessary to interpret a response rate fully; those primary-result details 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")
n      <- c(30)
events <- c(26)
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  30  26  86.7  69.3  96.2  70.3  94.7  70.2  94.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures overall. Major Response Rate is identified as the primary outcome, and Duration of Response is listed as a secondary outcome. The titles and analysis results for the other outcome measures are not reported in the registry information. The number of analyses recorded is 0.

Multiplicity arises when several outcomes, timepoints, subgroups, or statistical tests are considered. In general, the more opportunities there are to identify a result as statistically notable, the more important it is to specify in advance which outcomes are primary and how multiple testing will be handled. The registry identifies a primary endpoint, but a multiplicity strategy or hierarchy for the other outcomes is not reported in the registry record. It would therefore be inappropriate to assume that adjustments were or were not made in any analysis beyond what is recorded.

Missing-data rules are also not reported. The primary population description excludes one participant determined to be ineligible, but it does not explain how missing endpoint assessments, withdrawals, or incomplete follow-up were handled. The final primary-endpoint denominator is not reported. No named efficacy analysis population or missing-data method is reported in the registry record.

The record does not report interim analyses or stopping rules. These details should not be inferred from the completed status or the study timeframe. Without the analysis population, missing-data approach, and multiplicity plan, readers cannot assess how these choices might affect the primary estimate or the interpretation of other outcomes. Most importantly, the registry does not report the primary response estimate itself.

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: atrial fibrillation (6.5%), ast elevation (6.5%), alt elevation (6.5%), head trauma (3.2%), mania (3.2%).

For the Ibrutinib group, the registry lists 31 participants at risk for serious adverse events and 15 affected. For other adverse events, it lists 31 at risk and 31 affected. The death count is 0. These are separate registry safety summaries; the affected counts should not be added together because the record does not say whether participants appear in more than one category.

The serious-event terms reported with percentages are atrial fibrillation, AST elevation, and ALT elevation, each at 6.5%; head trauma, mania, and non-cardiac chest pain, each at 3.2%. The registry does not report participant counts for each listed term in the information. These term-level percentages should not be confused with the overall count of participants affected by serious adverse events.

Adverse-event reporting describes events recorded during the study; it does not by itself establish that the intervention caused them. The registry record does not provide a comparison group for safety rates, and the posted figures should not be interpreted as comparative risks.

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

The registry record documents a Phase II investigation of ibrutinib in symptomatic, previously untreated WM and defines a primary response outcome based on serum IgM reduction. It also describes the study as single-group, open label, and single center. These details explain what the study was designed to examine, but they do not establish the result of the primary endpoint.

The key efficacy limitation in the registry information is that the Major Response Rate result is not reported. There is no response count, percentage, uncertainty interval, or primary-endpoint analysis to interpret. As a result, the registry record does not show how often participants met the response definition or how precisely that frequency was estimated. The listed endpoint definition cannot substitute for an observed result.

Even if a response estimate were available, this single-group design would describe outcomes among the participants studied rather than provide a randomized comparison with another treatment. It would not by itself establish a causal treatment effect. The registry also lists Duration of Response as a secondary outcome without reporting its result, so the information does not establish how long responses lasted.

The safety information gives counts of participants affected by serious and other adverse events and lists selected serious-event terms with percentages. These descriptions are useful for understanding what the registry records, but without a control group they do not provide a comparative safety estimate or establish causation. The figures do not, by themselves, establish an overall balance of benefits and harms.

The record's completed status means the study is listed as completed; it does not mean that every result is reported in the registry. The appropriate statistical conclusion is limited: the design and outcome definitions are described, and some safety counts are posted, while the primary response result and its precision are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable for the contrast between a clearly specified response question and the absence of a posted primary response result. The endpoint defines major response as Partial Response, based on a 50% reduction or more in serum IgM, or better. That gives readers a threshold for understanding what the study intended to count. The record also specifies the primary-outcome timeframe and describes the population as excluding one participant determined to be ineligible.

The single-group structure is important to interpretation. In general, an uncontrolled study can describe outcomes in the treated cohort, but it cannot provide the same treatment contrast as a randomized comparison. The registry identifies no comparator and no masking. Those design features should be kept in view if results become available; they cannot be repaired by a planning illustration or by interpreting the endpoint definition as a result.

The record also illustrates why effect estimates and uncertainty matter. A response count alone would not communicate precision, and a percentage needs a clearly stated denominator. Here, neither the primary result nor its uncertainty is reported. The six listed outcome measures and the absence of recorded analyses also leave the analysis and multiplicity approach unclear.

Finally, the posted safety counts are distinct from the missing efficacy result. Serious and other adverse events have separate at-risk and affected figures, while selected serious-event terms have percentages. Keeping these summaries separate avoids treating safety counts as evidence about response. The trial's statistical importance for readers is therefore chiefly methodological: it shows why design, endpoint definition, analysis population, outcome estimates, and uncertainty need to be considered together.

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 are specific to the design and registry information for this study. It is described as single arm, open label, and single center, with no randomized control group. Outcomes from this design cannot provide a like-for-like comparison with another treatment, and the registry record does not report a comparative treatment effect. The population is people with symptomatic, previously untreated WM, so the record does not establish how the findings would apply to populations outside that description.

Enrollment is listed as 31, while the primary-outcome population excludes one participant determined to be ineligible. The record does not give the final analysis denominator or explain how missing endpoint assessments were handled. It also does not report the primary response count, percentage, confidence interval, or analysis method. That omission prevents assessment of both the observed response and its statistical precision.

The registry lists six outcome measures, identifies Duration of Response as secondary, and records 0 analyses. It does not report a multiplicity plan, interim analyses, or a trial-specific sample-size justification. The planning assumptions describe an illustrative two-arm calculation, whereas the trial itself is recorded as single group; those planning assumptions do not supply a controlled comparison or an observed-power result.

The posted safety counts and selected serious-event percentages do not establish causation or comparative safety in the absence of a control group. In addition, the registry record does not report the results for Duration of Response or the other outcome measures. These gaps limit interpretation of efficacy, durability, and the overall statistical evidence available from the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing — NCT02604511.
• Registry record last updated 2022-12-07; status last verified 2022-12.
• Results first posted 2022-01-12.
• 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

NCT02604511 is a completed Phase II, single-group, open-label, single-center study of ibrutinib in symptomatic, previously untreated Waldenstrom's Macroglobulinemia. Enrollment is listed as 31; the recorded start is 2016-01 and primary completion is 2022-11-01. Treatment is described as being administered in 4-week cycles for up to 48 cycles.

The primary outcome is Major Response Rate over 4 years, defined as Partial Response—a 50% reduction or more in serum IgM—or better. The primary population excludes one participant determined to be ineligible. The registry record does not report the response count, rate, or analysis. Duration of Response is listed as a secondary outcome, and six outcome measures are recorded overall.

For safety, the Ibrutinib group lists 15 participants affected by serious adverse events among 31 at risk, 31 affected by other adverse events among 31 at risk, and 0 deaths. The record provides selected serious-event terms with percentages but no randomized comparator. Consequently, it describes the study design, endpoint, and posted safety information without reporting a primary efficacy estimate or comparative treatment effect.