Post-Transplant Bortezomib and High Dose Cyclophosphamide as Graft-Versus-Host Disease (GVHD) Prophylaxis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Post-Transplant Bortezomib and High Dose Cyclophosphamide as Graft-Versus-Host Disease (GVHD) Prophylaxis (NCT01860170), a non-randomized phase 1, phase 2 study. The primary outcome is Dose Limiting Toxicity.

2. Clinical Question

3. Trial Design

This was a completed, nonrandomized parallel-cohort study listed as phase I and phase II. The registry records enrollment of 28 participants and identifies Corewell Health West as sponsor. The study started in 2012-04 and primary completion was in 2016-03. The target setting was reduced-intensity allogeneic hematopoietic stem cell transplantation, with GVHD prevention as the purpose of the post-transplant regimen.

Three cohorts received different recorded bortezomib doses: 0.7 mg/m2, 1 mg/m2, and 1.3 mg/m2. The arm descriptions specify rapid IV push on days 0 and +3, with administration on day 0 at least 6 hours after transplant. The registry title and summary describe bortezomib in combination with high-dose cyclophosphamide. Details of cyclophosphamide administration are not reported in the registry record.

Allocation was nonrandomized and masking was none. These features matter when interpreting differences among cohorts. Because participants were not randomly allocated, cohort outcomes can reflect more than dose level; the registry does not report enough information to assess the extent of such differences. The cohorts are not a like-for-like control comparison, and no separate control group is described.

The primary outcome was dose-limiting toxicity, expressed as a participant count. The assessment timeframe was daily while inpatient, using clinical and laboratory examination, up to 90 days. Engraftment is listed as a secondary outcome. The registry does not report the protocol’s cohort assignment procedures, dose-escalation rules, sample-size justification, interim analyses, or detailed statistical analysis plan.

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

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 Dose Limiting Toxicity, measured over Assessed daily (while inpatient) through clinical and laboratory examination up to 90 days..

The primary endpoint is dose-limiting toxicity, reported as the count of participants meeting the specified toxicity definition. The definition includes Grade 3 non-hematologic Common Toxicity Criteria toxicity directly related to bortezomib, with peripheral neuropathy given as an example. The record also includes the wording “Grade 2 or > hepatic bilirubin Common Toxicity Criteria Graft failure.” The relationship among those terms is unclear as written; a more detailed interpretation of that criterion is not reported in the registry record.

The endpoint is suited to a dose-finding context because it captures serious toxicity concerns that may limit use of a dose. A participant count indicates how many people met the definition, while the assessment period explains when investigators looked for qualifying events. The recorded schedule was daily while inpatient through clinical and laboratory examination up to 90 days.

General statistical context: an endpoint definition must be sufficiently precise for consistent classification. Differences in how investigators interpret an unclear criterion can affect which participants are counted. The registry does not report the observed number meeting the primary endpoint, cohort-specific endpoint results, or the analysis used to compare doses. As a result, the registry record does not establish how often dose-limiting toxicity occurred in this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a nonrandomized parallel design with no masking. The study has phase I and phase II designations and three bortezomib dose cohorts. These labels describe the recorded design; the registry does not state the precise procedures used to assign participants to cohorts or whether the phases followed a particular escalation scheme. Such details should not be inferred from the dose levels alone.

What does nonrandomized allocation mean?

General statistical context: randomization is used to distribute measured and unmeasured participant characteristics across treatment groups by chance. In a nonrandomized study, group membership can be related to clinical judgment, timing, eligibility, or other factors. Those factors can also be associated with outcomes, creating confounding. The registry record does not report the assignment mechanism or participant characteristics by cohort, so the potential for confounding cannot be assessed from the posted information.

The parallel model means the study describes separate cohorts rather than a within-participant comparison. However, because allocation was nonrandomized, the cohorts are not automatically comparable. The registry itself cautions that the arms are not a like-for-like control comparison. Thus, observed differences in safety counts should not be attributed to dose without a design and analysis that addresses other explanations.

How should the endpoint be understood?

The primary endpoint is a binary participant-level outcome presented as a count: participants either meet the dose-limiting toxicity definition or do not. The listed assessment period is daily while inpatient, with clinical and laboratory examination up to 90 days. The registry gives examples and grading language for the qualifying events, but the wording of the hepatic bilirubin and graft-failure criterion is unclear. A complete operational definition and adjudication procedure are not reported in the registry record.

General statistical context: binary outcomes are often summarized by counts and proportions, and may be compared using statistical tests or models. Such analyses require clear definitions of the outcome, denominator, and analysis population. The registry does not report primary endpoint counts or analyses, so no effect estimate or uncertainty interval can be interpreted. Engraftment is listed as a secondary outcome, but its definition, timing, and results are not reported.

What can event counts tell the reader?

The adverse-event record gives participants at risk, participants affected, and deaths for each dose cohort. These values permit a descriptive reading of how many participants were recorded in each category. They do not tell whether an event was caused by treatment, whether the same participant experienced multiple events, or whether events differed in severity beyond the registry’s serious-event classification. Timing, event duration, and causal attribution are not reported.

General statistical context: a count depends on its denominator and follow-up. A cohort with more participants can have more recorded events even when its event frequency is not higher. Conversely, proportions based on small denominators can change substantially when a single participant’s status changes. Comparing cohorts requires attention to the denominator, the length and completeness of follow-up, event definitions, and cohort comparability. The registry does not provide enough information to evaluate all of these features.

Why does over-dispersion matter?

General statistical context: over-dispersion arises when observed variability in count data is greater than a statistical model expects. It can make standard errors too small if the model assumes less variability than the data contain. This trial’s primary endpoint is recorded as a participant count, but no fitted model or count analysis is reported. Over-dispersion is therefore a general consideration, not a finding about this trial.

What can confidence intervals and significance tests establish?

General statistical context: a confidence interval expresses uncertainty around an estimated quantity under a specified method and assumptions. A significance test assesses how compatible data are with a stated null model; it does not establish causation or clinical importance. Neither an interval nor a test is reported for the primary endpoint in the registry record. No p-value or adjusted analysis is available to interpret.

The record does not report a sample-size justification, target power, interim analyses, or a detailed statistical plan. Those omissions prevent assessment of whether the study was designed to estimate toxicity rates with a particular precision or to test a specified dose comparison. The total enrollment and cohort denominators are descriptive details, not evidence of a particular power or precision target.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1-Bortezomib (Velcade®)", "Cohort 2-Bortezomib (Velcade®)", "Cohort 3-Bortezomib (Velcade®)")
n      <- c(3, 3, 22)
events <- c(0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1-Bortezomib (Velcade®)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 2-Bortezomib (Velcade®)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 3-Bortezomib (Velcade®)  22  0  0.0  0.0  15.4  -0.0  14.9  0.1  14.8

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study assesses several outcomes, doses, time points, or statistical comparisons. Repeated testing can increase the chance of obtaining an apparently notable result by chance. The registry lists dose-limiting toxicity as the primary outcome and engraftment as a secondary outcome. It does not report the planned statistical tests, the number of planned comparisons, or any method for controlling multiplicity. No multiplicity adjustment is reported in the registry record.

Missing-data handling is also not reported. The registry does not describe how incomplete toxicity assessments, withdrawals, lost follow-up, or missing laboratory measurements were handled. It also does not report whether participants were analyzed according to an intention-to-treat, per-protocol, safety, or other analysis population. The adverse-event denominators indicate participants at risk for those listings, but they do not define the analysis population for the primary endpoint.

The registry records no statistical analyses. It does not report how exclusions were handled, how outcomes were summarized, or whether any adjustment was made for participant characteristics. It also does not describe sensitivity analyses, interim monitoring, or a prespecified hierarchy among outcomes. These absences limit interpretation: readers cannot determine whether reported safety counts reflect all enrolled participants, a defined subset, or a particular follow-up rule beyond the denominators attached to the adverse-event groups.

General statistical context: a prespecified analysis plan helps distinguish planned analyses from choices made after outcomes are observed. Clear missing-data rules help readers understand who contributed to each estimate and whether incomplete follow-up could affect the result. Without these details, the registry supports descriptive reading of the counts but not a full assessment of analysis reliability.

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: fever (33.3%), hsv (33.3%), syncope related to anemia (33.3%), progressive multifocal leukoencephalopathy (4.5%), hypovolemic shock (4.5%).

The registry reports serious adverse-event counts by bortezomib cohort: 2 of 3 participants at risk in the 0.7 mg/m2 cohort, 1 of 3 in the 1 mg/m2 cohort, and 6 of 22 in the 1.3 mg/m2 cohort. It also reports other adverse-event counts of 1 of 3, 2 of 3, and 19 of 22, respectively. Death counts are 0, 3, and 10. These categories should be read as registry-recorded counts, not as proof that treatment caused the events or deaths.

The term-specific serious-event list names Fever, HSV, and Syncope related to anemia at 33.3% each, and Progressive multifocal leukoencephalopathy, Hypovolemic shock, and Atrial fibrillation at 4.5% each. The registry does not clarify the denominator, whether the percentages apply across cohorts or separately, or how repeated events in one participant were handled. It also does not report timing, duration, cause, or attribution for these events.

General statistical context: safety summaries depend on who was followed, for how long, and how events were defined and recorded. Cohort sizes differ, so raw counts are not direct comparisons of event frequency. These figures are descriptive and should not be used alone to infer relative safety across dose levels.

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

The registry record describes a trial designed to examine bortezomib dose levels with high-dose cyclophosphamide for GVHD prophylaxis after reduced-intensity allogeneic hematopoietic stem cell transplantation. It specifies three bortezomib cohorts and a primary endpoint based on participants meeting a dose-limiting toxicity definition. It also records adverse-event and death counts by cohort. These details establish what the study set out to examine and what safety summaries were entered in the registry.

The posted record does not report observed results for the primary endpoint or the secondary outcome of engraftment. It therefore does not show how many participants met the dose-limiting toxicity criteria or provide a statistical estimate comparing dose cohorts. Although adverse-event counts are listed, they do not alone establish that bortezomib or the combination caused an event. The nonrandomized design further limits causal interpretation because the groups may differ in ways not described in the registry.

General statistical context: a study’s observed data can support different kinds of conclusions depending on its design, measurement quality, and analysis. Descriptive event counts answer how many participants were recorded in a category, subject to the definitions and follow-up used. Comparative claims require an appropriate comparison and an analysis that addresses uncertainty and potential confounding. The registry does not report those analyses.

The information also does not establish the precision of the primary endpoint estimate, because no endpoint estimate or confidence interval is reported. The enrollment and cohort denominators should not be treated as an observed-power calculation or as evidence that a particular dose is safe, unsafe, effective, or ineffective. The record does not report a dose-selection conclusion or a recommendation for clinical use.

Accordingly, the trial’s registry entry is most informative as a description of its design, dosing cohorts, endpoint definition, and recorded safety counts. It leaves important questions about outcome results, event attribution, participant comparability, missing data, and statistical analysis unanswered. Those limits should remain part of any interpretation.

14. Why This Trial Matters Statistically

This trial raises a central statistical challenge in early dose evaluation: distinguishing a possible dose-related safety pattern from variation that may arise from small groups, different participants, or incomplete information. Its three cohorts used different recorded bortezomib doses, but allocation was nonrandomized. That design feature is important because apparent differences between cohorts cannot automatically be interpreted as effects of dose.

The primary endpoint focuses on dose-limiting toxicity, an outcome relevant to assessing tolerability in a dose-focused study. Yet the registry does not report the endpoint counts or a dose comparison. The safety summaries therefore cannot answer the primary statistical question. The recorded serious adverse-event counts and deaths provide descriptive information, but without attribution, timing, and cohort comparability they do not establish a dose-response relationship.

General statistical context: small cohorts can produce unstable estimates, and uncertainty is particularly important when outcomes are uncommon. A clear outcome definition, complete follow-up, and transparent analysis plan are needed to make safety estimates interpretable. The registry’s wording for part of the toxicity criterion is unclear, while missing-data and analysis-population procedures are not reported. Those details can affect both which participants are counted and how conclusions are drawn.

The entry also illustrates why registration information and posted results are distinct. A registry can describe the planned question, design, and outcome measures, while still not reporting the results or analyses needed to evaluate an estimate. For this study, the record supports discussion of design limitations and descriptive event reporting, but not a statistical conclusion about the primary endpoint or the relative performance of dose cohorts.

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 specific to this trial constrain interpretation. The study was nonrandomized and unmasked, and its cohorts are not a like-for-like control comparison. Participant characteristics by cohort and the cohort assignment mechanism are not reported, so potential confounding cannot be evaluated. The record describes three dose levels but does not report the rules used to assign participants or whether dose escalation followed a prespecified procedure.

The primary endpoint results are not reported in the registry record. The entry gives the dose-limiting toxicity definition and timeframe, but part of the hepatic bilirubin and graft-failure wording is unclear. No adjudication process or operational clarification is reported. Engraftment appears as a secondary outcome, but its result and assessment details are not reported.

The safety information lacks details needed for comparison, including event timing, duration, attribution, and causes of death. The record does not explain the denominator for the percentages attached to serious-event terms or whether the terms are distributed across cohorts. Follow-up completeness and missing-data procedures are not reported. The denominators in the safety listing do not, by themselves, establish the primary endpoint analysis population.

No statistical analyses are recorded. The registry does not report a sample-size justification, statistical plan, multiplicity handling, interim analyses, uncertainty intervals, or adjustment for potential confounding. These omissions mean that the reported counts cannot be converted into a supported comparative or causal conclusion. The enrollment of 28 participants is a descriptive study fact, not evidence of a particular precision target or observed power.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Post-Transplant Bortezomib and High Dose Cyclophosphamide as Graft-Versus-Host Disease (GVHD) Prophylaxis — NCT01860170.
• Registry record last updated 2023-06-02; status last verified 2023-05.
• Results first posted 2017-05-17.
• 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 completed study, NCT01860170, is listed as phase I and phase II, with nonrandomized allocation, no masking, and a parallel model. It enrolled 28 participants and evaluated three bortezomib dose cohorts alongside high-dose cyclophosphamide for GVHD prophylaxis after reduced-intensity allogeneic hematopoietic stem cell transplantation. The primary outcome was dose-limiting toxicity assessed daily while inpatient through clinical and laboratory examination up to 90 days. Engraftment was listed as a secondary outcome.

The registry records serious and other adverse-event counts and deaths by cohort, but does not report the primary endpoint results, engraftment results, or statistical analyses. Details of the analysis plan, missing-data handling, analysis populations, and sample-size justification are not reported in the registry record.