Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma (NCT03646123), a non-randomized phase 2 study. The primary outcome is Complete Response (CR) Rate at EOT (Parts B and C).

2. Clinical Question

3. Trial Design

This was a Phase 2, non-randomized, open-label, parallel study titled “Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma.” The registry lists enrollment of 255 and status as terminated. The recorded start date is 2019-01-28, and the primary completion date is 2022-11-07. The reason for termination is not reported in the registry record.

The study had three parts with distinct treatment regimens and populations. Part A evaluated A+AVD, combining brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine in participants with advanced-stage cHL. G-CSF was planned after every dose for 6 cycles of treatment, or 12 doses. Its stated focus was febrile neutropenia.

Parts B and C evaluated AN+AD: brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine. Part B enrolled participants with Stage II bulky mediastinal disease and Stage III or IV cHL. Part C enrolled participants with Stage I or II cHL with non-bulky mediastinal disease. The primary endpoint, CR rate at EOT, applied to Parts B and C. The registry describes these parts as studying how well the combination treats cHL and what side effects occur.

Because allocation was non-randomized and masking was absent, the record does not describe a blinded randomized efficacy comparison. The reasons for choosing the design, the allocation procedure beyond its non-randomized designation, and details of treatment-cycle schedules for Parts B and C are not reported in the registry 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: In this study participant's treatment was completed before primary completion date (PCD), and no treatment was administered after PCD, participants were followed up.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: For Part A, the full analysis set included all participants who received at least 1 dose of A+AVD (any of the study drugs in the regimen).

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 Response (CR) Rate at EOT (Parts B and C), measured over 7.8 months.

The primary endpoint was the percentage of participants with a complete response at end of treatment in Parts B and C. The registry specifies a timeframe of 7.8 months. CR was defined using the Lugano Classification Revised Staging System for malignant lymphoma, with incorporation of the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). The endpoint applied to participants with previously untreated cHL.

A response-rate endpoint describes the proportion of a defined analysis population who meet a stated response criterion at a specified assessment. It gives a direct summary of response status at that assessment, but by itself does not describe how long a response lasts or what happens after treatment ends. General statistical interpretation: the percentage is an estimate for the participants represented in the analysis; its precision depends in part on how many participants contribute usable endpoint data.

The registry record gives the endpoint definition and its 95% confidence interval as the stated measure of precision, but it does not report the CR estimate or confidence interval. It also does not report how many participants in Parts B and C had an assessment adequate for this endpoint. As a result, the endpoint’s observed value and precision cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: a response rate is a binary-outcome summary. Each participant contributes a response classification, such as CR or not CR, under the endpoint definition. The rate is the percentage of the analysis population classified as having the response. The registry identifies the primary endpoint as a percentage and specifies a 95% confidence interval, but does not post the numerical estimate or interval.

What does a confidence interval communicate?

General: a confidence interval expresses uncertainty around an estimated quantity. A narrower interval indicates greater statistical precision than a wider interval, while neither width nor location alone establishes clinical importance. Interpreting an interval requires the point estimate, the interval limits, and an understanding of the population and endpoint. Here, the registry record does not report the CR estimate or the 95% confidence interval, so its precision cannot be assessed.

Why does the analysis population matter?

The registry defines the full analysis set for Parts B and C as all participants who enrolled and received any amount of the combination therapy in the study. This definition identifies who was intended to contribute to those parts’ analyses. It is not a statement that every enrolled participant had an assessable EOT response, nor does it explain how missing or unevaluable response assessments were handled. Those details are not reported in the registry record. The analysis population for Part A is not reported in the registry record.

What can non-randomized allocation support?

General: random allocation can help balance measured and unmeasured prognostic factors across treatment groups, on average. In a non-randomized study, treatment assignment may be associated with participant characteristics or clinical decisions. Consequently, an observed difference between groups can reflect differences in their populations as well as differences in treatment. This concern is especially relevant when parts have distinct eligibility characteristics and regimens. The record describes a non-randomized parallel design and explicitly cautions that the arms are not a like-for-like control comparison. An adjusted comparative analysis is not reported in the registry record.

How should planning calculations be read?

The planning assumptions described for sample-size illustrations use 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. For time-to-event illustrations, the stated quantity is total events using the Schoenfeld method; other illustrations are expressed as participants per arm. These are planning illustrations based on an observed effect, not the trial’s own design or evidence of observed power. The record does not report the trial’s sample-size justification. Since the primary CR estimate is not reported in the registry record, the actual result and its relation to any planning illustration cannot be evaluated from that record.

What is not specified about the statistical methods?

General: binary outcomes can be summarized with a response proportion and an interval estimate, but several choices affect the result, including the interval method, handling of missing outcomes, and the analysis population. The registry record does not specify the method used to calculate the primary confidence interval, how missing endpoint assessments were handled, or whether any covariate adjustment was used. It also does not report a statistical analysis plan, interim analyses, or a reason for selecting a particular method. No such details should be inferred from the endpoint definition alone.

The record lists 22 outcome measures and 0 analyses. That distinction matters: outcome definitions describe what was intended to be measured, whereas numerical analyses report what was observed and how it was estimated. Without posted primary estimates, confidence limits, or analysis details, the statistical evidence for the primary endpoint cannot be independently characterized from 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("Part B", "Part C")
n      <- c(57, 154)
events <- c(50, 142)
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  Part B  57  50  87.7  76.3  94.9  76.8  93.9  76.7  93.9
ARM  Part C  154  142  92.2  86.8  95.9  86.9  95.5  86.9  95.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures, including the primary CR rate for Parts B and C and secondary outcomes in Part A. The Part A secondary outcomes include adverse events of clinical interest, primary refractory disease rate, CR rate, physician-reported progression-free survival, subsequent anticancer therapy utilization, and dose-intensity measures. The registry record lists 0 analyses, so numerical findings for these outcomes are not available in the posted results.

Multiplicity arises when several outcomes or repeated statistical tests are considered. General statistical explanation: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan accounts for the testing structure. A multiplicity strategy, such as a prespecified hierarchy or adjustment, can clarify which findings are confirmatory and how uncertainty should be interpreted. The multiplicity strategy for this study is not reported in the registry record. The number of outcome measures alone does not establish how many formal tests were conducted.

The registry defines the Parts B and C full analysis set as participants who enrolled and received any amount of combination therapy. It does not report the number with an evaluable EOT response or the handling of missing response assessments. Missing-data methods, reasons for missing assessments, and sensitivity analyses are not reported in the registry record. The analysis population for Part A is also not reported in the registry record.

These gaps prevent assessment of whether the posted primary endpoint estimate represents all intended participants, and how robust it might be to missing outcomes or multiple testing. Interim analyses and a statistical analysis plan are not reported 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: febrile neutropenia (12.5%), pneumonia (10.0%), pyrexia (7.5%), pneumonitis (5.3%), abdominal pain (5.0%).

The registry lists serious adverse event counts by study part. In Part A, 19 of 40 participants were affected; in Part B, 15 of 57; and in Part C, 29 of 154. For other adverse events, the corresponding counts were 40 of 40, 57 of 57, and 153 of 154. The record lists 2 deaths in Part A, 1 in Part B, and 1 in Part C.

These figures are descriptive counts within each part. The parts enrolled different populations and received different regimens, and the study was non-randomized. The counts therefore should not be read as a like-for-like safety comparison. The record does not establish whether deaths were caused by treatment, and the listed counts do not by themselves establish the severity, timing, duration, or clinical course of each event.

The serious adverse event terms listed with percentages are febrile neutropenia (12.5%), pneumonia (10.0%), pyrexia (7.5%), pneumonitis (5.3%), abdominal pain (5.0%), and pain (5.0%). These term percentages are descriptive. The registry record does not provide a comparative analysis or enough information in this listing to assign the percentages to a specific part or determine treatment causality.

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

The record establishes that this Phase 2 study evaluated distinct brentuximab vedotin-containing combinations across three parts of a non-randomized, parallel study. Part A focused on A+AVD and febrile neutropenia; Parts B and C studied AN+AD and used CR rate at EOT as the primary endpoint. The endpoint definition, eligible populations, and some adverse-event counts are reported.

What the record does not establish is the numerical primary CR rate or its 95% confidence interval. The registry record does not report those results, and it lists 0 analyses. Consequently, the primary endpoint’s observed magnitude and statistical precision cannot be assessed. The record also does not report a numerical result for the Part A focus on febrile neutropenia.

General statistical interpretation: an endpoint definition is not an outcome result. A planned measure explains what investigators intended to assess; it does not show what participants experienced. Likewise, a confidence interval is useful only when its estimate and limits are available, and a descriptive count does not establish a causal treatment effect.

The safety counts can describe events recorded within each part, but they do not demonstrate that one regimen is safer than another. The study was non-randomized, the parts enrolled different populations, and the registry does not report a like-for-like control comparison. The death counts do not, by themselves, identify cause or treatment attribution.

Accordingly, the posted information supports a description of study conduct and selected safety counts, not a conclusion that a treatment did or did not work. It also does not support a comparative estimate of benefit or harm between the regimens. The reason for termination and the missing statistical and endpoint results remain not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why a clinical endpoint, a study design, and a posted analysis must be considered together. The primary CR endpoint is defined for Parts B and C, including the assessment timing and response criteria. Yet the registry record does not report the numerical estimate or its confidence interval. A clearly defined endpoint alone cannot show the magnitude or precision of the observed response.

The non-randomized, multi-part design is also important for interpretation. The parts studied different combinations and populations defined by disease stage and mediastinal disease characteristics. Their results cannot be treated as a randomized comparison of interchangeable groups. This is a statistical limitation on causal interpretation, not merely a reporting detail.

The safety record offers another practical lesson: counts and percentages need context. Serious adverse event counts are listed by part, while a separate list gives percentages for selected serious event terms. Those summaries are descriptive and do not supply a comparative treatment effect or establish causation. Denominators, analysis populations, and event definitions are essential to interpreting safety summaries appropriately.

Finally, the record separates outcome planning from numerical analysis: it lists 22 outcome measures but 0 analyses. Statistical literacy requires distinguishing what was measured from what was estimated, and distinguishing a planning illustration from observed power or a protocol’s sample-size justification. These distinctions help prevent unsupported claims when registry information is incomplete.

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 main trial-specific limitation in the registry record is the absence of numerical primary endpoint results. The CR rate at EOT and its 95% confidence interval are not reported, and the record lists 0 analyses. The reason for termination is also not reported in the registry record, so the status cannot be explained from the posted information.

The design was non-randomized and open-label. The parts involved different populations and treatment combinations, and the registry notes that the arms are not a like-for-like control comparison. Consequently, cross-part differences would not provide a clean causal comparison. The registry does not report an adjusted comparison or other method intended to address differences between populations.

Further details needed to assess endpoint reliability are not reported in the registry record, including the number of participants with evaluable EOT assessments, the handling of missing data, the confidence-interval method, and sensitivity analyses. The Part A analysis population and numerical results for its stated febrile-neutropenia focus are also not reported.

The record lists adverse-event counts and selected term percentages, but does not establish causal attribution for deaths or provide a comparative safety analysis. A statistical analysis plan, multiplicity approach, interim analyses, and the trial’s sample-size justification are not reported in the registry record. These reporting gaps limit interpretation of both efficacy and safety beyond descriptive study information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma — NCT03646123.
• Registry record last updated 2025-08-28; status last verified 2025-08.
• Results first posted 2023-12-21.
• 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 NCT03646123, a Phase 2, non-randomized, open-label, parallel study of brentuximab vedotin combinations in cHL. Enrollment was 255; status is terminated. The recorded start date is 2019-01-28 and primary completion date is 2022-11-07.

Part A studied A+AVD with G-CSF and focused on febrile neutropenia. Parts B and C studied AN+AD in distinct disease-stage populations. Their primary endpoint was CR rate at EOT, defined using the stated Lugano and LYRIC criteria, with a 7.8 months timeframe.

The numerical primary endpoint result and confidence interval are not reported in the registry record, which lists 0 analyses. Serious adverse event counts and selected event-term percentages are posted, but they do not constitute a randomized comparison or establish treatment causality.