Dose Finding Study of Vedolizumab for GvHD in Participants Undergoing Allogeneic HSCT: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Finding Study of Vedolizumab for GvHD in Participants Undergoing Allogeneic HSCT (NCT02728895), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

The study was designed to assess initial tolerability and safety and to identify a recommended phase 2 dose for vedolizumab used as GvHD prophylaxis with standard prophylaxis therapy. The population of interest was people undergoing allo-HSCT, a setting in which the registry describes GvHD prophylaxis as the intended use of the study treatment. The primary question is therefore about observed safety events during the stated early follow-up window, rather than a comparison of clinical benefit between treatment and control.

The dose-finding structure included Cohort 1, receiving vedolizumab 75 mg, and Cohort 2, receiving 300 mg. Cohort 3 received the first decided dose determined from Cohort 1 or Cohort 2. These descriptions indicate that dose selection was part of the study’s purpose, but the registry record does not report which dose was selected for Cohort 3 or the rationale for that selection.

The registry record does not report a randomized comparator, and the listed groups should not be interpreted as randomized treatment arms. It also does not report the number of participants with DLTs. Accordingly, the primary clinical question can be stated from the endpoint definition, but the posted record does not give a result that answers it.

3. Trial Design

This was a phase 1, open-label, non-randomized, parallel study sponsored by Takeda. Its stated purpose was to assess the initial tolerability and safety of intravenous vedolizumab used with standard GvHD prophylaxis, and to identify a recommended phase 2 dose in participants undergoing allo-HSCT. The registry lists an enrollment of 24 and a completed status. The recorded start date is 2016-06-15, and the primary completion date is 2018-07-10.

The listed dose groups were Cohort 1: vedolizumab 75 mg, Cohort 2: vedolizumab 300 mg, and Cohort 3: a first decided dose selected from Cohort 1 or Cohort 2. Each description specifies an intravenous dose on Days -1, 13 and 42. Standard GvHD prophylaxis was given alongside vedolizumab according to the study summary. The registry record does not detail the specific standard prophylaxis treatments.

Non-randomized allocation means participants were not assigned to the listed groups by random allocation, according to the record. Open-label means the study is listed as having no masking. These features matter when interpreting differences between cohorts: group membership may reflect dose-finding decisions, and there is no randomized control group to provide a like-for-like comparison. The registry itself cautions that the arms are not a like-for-like control comparison.

The primary endpoint was the number of participants with DLTs from baseline up to Day 28. The registry defines the safety-evaluable population as all participants who received any amount of intravenous vedolizumab. Secondary outcomes included time to neutrophil engraftment, measures of acute GvHD severity, and vedolizumab trough serum concentration. Although the record lists eight outcome measures, it reports zero analyses. The registry record does not report a statistical analysis plan, the dose-escalation decision rules, or a sample-size justification.

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: Participants undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) were enrolled to receive vedolizumab intravenous 75 milligram (mg) or 300 mg along with standard graft-versus-host disease (GvHD) prophylaxis therapy (tacrolimus plus short team methotrexate).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.

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: The population of participants evaluable for vedolizumab safety was defined as all participants who received any amount of vedolizumab intravenously.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicities (DLTs), measured over Baseline up to Day 28.

The primary endpoint is the number of participants with dose-limiting toxicities (DLTs) from baseline up to Day 28. A DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The definition included toxicity of Grade 3 or higher that the investigator assessed as related to vedolizumab, regimen-related organ toxicity of Grade 4 or higher, or failure to engraft by Day +28.

For the engraftment component, the record defines engraftment as an absolute neutrophil count greater than 500 per cubic millimeter for 3 consecutive days or greater than 2000 per cubic millimeter for 1 day. The endpoint combines toxicity and failure-to-engraft criteria into a count of participants meeting at least one of the specified DLT conditions. It is a count endpoint, not a time-to-event estimate or a comparison of average values.

In a dose-finding study, a DLT endpoint is used to describe early tolerability at the doses under evaluation and to inform dose selection. That general purpose does not establish that any particular dose is tolerable or appropriate. The registry record gives the endpoint definition and timeframe but does not report the number of participants with DLTs, the number evaluated for this endpoint, or dose-specific DLT results. The posted record therefore does not provide the observed primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is limited. It identifies a binary primary endpoint expressed as a count of participants with an event, gives the endpoint definition and timeframe, and lists secondary outcomes. It also lists zero analyses. The registry record does not report the statistical methods used for the primary or secondary outcomes, a prespecified analysis plan, or inferential results such as confidence intervals or p-values.

What does a count endpoint describe?

The primary endpoint is the number of participants meeting the DLT definition, not the number of separate toxicity events. This distinction matters in general because one participant may experience more than one event, while a participant-level endpoint counts that person once if the endpoint definition is met. The record names the endpoint as a count of participants, but gives no observed count. It also defines the safety-evaluable population as participants who received any amount of intravenous vedolizumab; the record does not report how many participants were included in the primary endpoint calculation.

The endpoint combines specified categories: investigator-assessed vedolizumab-related toxicity at Grade 3 or higher, regimen-related organ toxicity at Grade 4 or higher, and failure to engraft by Day +28. A composite endpoint can gather clinically distinct events into one summary, but its overall count does not show which component occurred. Component-level results would be needed to distinguish the types of events contributing to any total. Such results are not reported in the registry record.

Why does the endpoint window matter?

The primary timeframe is baseline up to Day 28. A result for this window would describe DLTs meeting the definition during that stated period, rather than later outcomes over the full course of follow-up. A short-term endpoint can be relevant in early dose-finding, where initial safety is the stated focus. It does not, by itself, describe every potential safety outcome or establish longer-term safety. The registry record does not provide additional follow-up details for the primary endpoint.

Engraftment is incorporated through a specific threshold and duration rule: an absolute neutrophil count greater than 500 per cubic millimeter for 3 consecutive days or greater than 2000 per cubic millimeter for 1 day. These thresholds are part of the registry’s operational definition. General statistical principle: a clear operational definition helps determine consistently which observations count as endpoint events, but the definition alone does not reveal how many participants met it.

What does non-randomized allocation imply?

The study is recorded as non-randomized, open-label, and parallel. General statistical principle: random allocation can reduce systematic differences between groups at baseline, while non-randomized allocation does not ensure that groups are comparable. In an open-label study, treatment is not masked according to the record. Assessment of investigator-related toxicity may therefore be susceptible to knowledge of treatment, although the registry does not report whether or how this was addressed. These design features limit causal interpretation of any differences between dose cohorts.

The registry describes a dose-finding sequence: one cohort received 75 mg, another received 300 mg, and a further cohort received a dose selected from those cohorts. The record does not report the decision rule for selecting the later dose or the number assigned to each cohort beyond the at-risk counts in the adverse-event summaries for Cohort 1 and Cohort 2. It does not report the selected dose for Cohort 3. No randomized control group is described.

How should uncertainty and planning calculations be read?

General statistical principle: estimates from small groups are often imprecise, and uncertainty is usually made visible with an interval estimate where one is available. The registry record gives no interval estimate for the primary endpoint. No uncertainty measure can be inferred from the fact that the study enrolled 24 participants.

The sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They specify that effects are framed as stated fractions of the observed effect, and that non-time-to-event illustrations are expressed as participants per arm. These are planning illustrations, not observed power and not evidence that the study was designed with those assumptions. The registry record does not report its own sample-size justification, and no numerical planning results are included in the registry record for this analysis.

General statistical principle: over-dispersion occurs when observed variability exceeds what a statistical model assumes. In count data, it can make conventional model-based uncertainty estimates too narrow if not accounted for. The record does not state that an over-dispersion model was used, and it does not provide a model or numerical outcome data that would allow this issue to be assessed for this trial.

What can be concluded from the listed analyses?

The registry lists eight outcome measures and zero analyses. The outcome list identifies what was intended to be measured, but does not establish that each outcome has a posted result. The primary DLT count and numerical results for the listed secondary outcomes are not reported in the registry record. General statistical principle: a descriptive result can communicate the observed data without a hypothesis test, while an inferential result requires a stated method and assumptions. Neither a descriptive primary endpoint result nor an inferential analysis is available 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("Cohort 1: Vedolizumab 75 mg", "Cohort 2: Vedolizumab 300 mg")
n      <- c(3, 21)
events <- c(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: Vedolizumab 75 mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 2: Vedolizumab 300 mg  21  0  0.0  0.0  16.1  -0.0  15.5  0.1  15.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures, including the primary DLT count and secondary measures of neutrophil engraftment, acute GvHD, and vedolizumab trough concentration. It lists zero analyses and does not report a statistical analysis plan. The record therefore does not explain whether outcomes were tested, how many comparisons were planned, or whether any adjustment for multiple testing was intended. Multiplicity procedures are not reported in the registry record.

General statistical explanation: when many outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase. An analysis plan can specify which outcomes are primary, how comparisons will be handled, and which results are exploratory. Here, the primary endpoint is identified, but the registry does not describe the inferential procedures or any multiplicity strategy. Since numerical outcome results are not reported, the impact of multiplicity on interpretation cannot be assessed.

The endpoint population is defined as all participants receiving any amount of intravenous vedolizumab. The registry record does not give a separate count of participants evaluated for the primary endpoint, describe missing endpoint data, or state how missing observations were handled. It does not report whether the secondary outcomes used the same population or different analysis populations. The record also does not state whether analyses followed an intention-to-treat principle, a per-protocol approach, or another named strategy; those terms should not be assigned to the study without documentation.

The record lists an enrollment of 24 and serious adverse-event at-risk counts for Cohort 1 and Cohort 2, but those figures do not fill in missing endpoint-analysis details. The registry record does not say whether all enrolled participants received treatment or contributed data to every outcome. Missing-data assumptions, sensitivity analyses, and reasons for missing observations 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: influenza (33.3%), diarrhoea (33.3%), nausea (33.3%), acute myeloid leukaemia recurrent (33.3%), failure to thrive (9.5%).

The adverse-event summary lists Cohort 1: vedolizumab 75 mg with 3 participants at risk for serious events and 2 affected; it lists 3 at risk for other events and 3 affected, with 1 death. Cohort 2: vedolizumab 300 mg has 21 participants at risk for serious events and 11 affected; it lists 21 at risk for other events and 21 affected, with 2 deaths. These are registry adverse-event counts and should not be confused with the primary DLT count, which is not reported.

The registry also lists serious-event terms with percentages: Influenza, Diarrhoea, Nausea, and Acute myeloid leukaemia recurrent are each listed as 33.3%; Failure to thrive and Febrile neutropenia are each listed as 9.5%. The record does not give further detail about event counts by term, whether a participant could contribute more than one term, or the denominator used for each percentage. General caution: adverse-event terms can describe events rather than unique participants, so a list of terms should not automatically be read as a list of mutually exclusive people.

The summaries do not establish causation. The registry record does not report whether each event was judged related to vedolizumab, and serious adverse events are not interchangeable with DLTs under the stated endpoint definition. The listed deaths are part of the adverse-event summary; the record does not provide causes or a relationship assessment for them.

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

The registry record establishes that this was a phase 1 dose-finding study of intravenous vedolizumab used with standard GvHD prophylaxis in people undergoing allo-HSCT. It specifies the primary safety endpoint, its Day 28 window, and the criteria used to define a DLT. It also documents the non-randomized, open-label design and lists adverse-event summaries for two dose cohorts. These features describe the study’s purpose and the kinds of observations recorded.

The posted results do not report the number of participants with DLTs. They also do not provide numerical results for the listed secondary outcomes or identify the dose selected for Cohort 3. Consequently, the record does not show the observed primary endpoint result or provide enough information to evaluate the reported tolerability question by dose. The serious adverse-event counts and listed terms do not replace the missing DLT result, because the endpoint definition is distinct and no mapping between serious events and DLTs is given.

The design does not support a randomized treatment-versus-control interpretation. The arms are not a like-for-like control comparison, and any apparent differences between the non-randomized cohorts would need to be interpreted in light of that design. The registry record does not provide the details needed to assess cohort comparability, adjustment methods, or uncertainty for between-cohort differences.

General interpretation: a registry entry can document planned outcomes and study characteristics without providing a complete results report. The absence of a reported result is not evidence that an outcome did or did not occur. It means that the registry record does not report the outcome, so its magnitude and precision cannot be assessed from this record. Nothing in the posted information establishes that vedolizumab does or does not prevent GvHD, or that one dose is preferable to another.

The sample-size illustrations are planning exercises rather than evidence of observed power. They do not supply the missing outcome data or justify a conclusion about the study’s findings. The registry record does not report its own sample-size justification, the analysis plan, or primary endpoint estimates with uncertainty. Interpretation should therefore remain limited to the design, definitions, and descriptive safety figures that are actually reported.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a dose-finding question and a comparative-effectiveness question. Its stated aim was to assess initial safety and tolerability and identify a recommended phase 2 dose. Its primary endpoint is a participant count based on toxicity and engraftment criteria during a defined early window. Those features set the intended scope: describe early safety observations across dose cohorts, rather than estimate a randomized treatment effect against a control group.

The design details matter for interpreting any cohort comparisons. Allocation was non-randomized, masking was absent, and the registry cautions that the arms are not a like-for-like control comparison. General statistical principle: a numerical contrast between non-randomized groups may reflect differences in who entered each group or how treatment decisions were made, as well as any treatment-related difference. Randomization and a clearly specified analysis can help address some sources of bias, but the record does not describe either a randomized comparison or an adjustment strategy.

The study also illustrates why outcome definitions and analysis results are both needed. The DLT definition is detailed, including toxicity grades and engraftment thresholds, but the number of participants meeting it is not reported. Without the observed count and its denominator, readers cannot assess the endpoint’s frequency or precision. A list of intended secondary outcomes likewise does not substitute for their numerical results.

The adverse-event summaries show why distinct safety summaries should not be conflated. Serious adverse events, other adverse events, deaths, and the composite DLT endpoint are different summaries in the record. Their counts may answer different questions, and the registry does not report whether the events overlap or meet the DLT criteria. Keeping these measures separate avoids attributing more meaning to the reported safety figures than their definitions support.

Finally, planning calculations and observed study results have different roles. The record’s stated assumptions for sample-size illustrations are not the trial’s documented design justification and are not observed power. In the absence of a reported primary outcome analysis, the statistical contribution of this registry record is chiefly its description of design, intended safety endpoint, and available adverse-event summaries.

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 is that the registry record does not report the primary endpoint result. Although it defines DLTs and gives the timeframe, it provides no count of participants meeting the definition, no cohort-specific DLT results, and no denominator for the primary endpoint analysis. This prevents assessment of the observed primary safety outcome and its precision.

The study was non-randomized and open-label, with no like-for-like control comparison. The record does not describe how participants entered each dose cohort, the dose-selection rules, or the selected dose for Cohort 3. These omissions limit interpretation of differences across cohorts and prevent reconstruction of the dose-finding decisions.

The record lists secondary outcomes but does not provide their numerical results. It also lists zero analyses and does not report the statistical analysis plan, methods for missing data, analysis populations for secondary outcomes, confidence intervals, or hypothesis tests. The sample-size justification is not reported in the registry record. The planning assumptions do not resolve those gaps and should not be read as observed power.

The serious adverse-event summary provides at-risk and affected counts for Cohort 1 and Cohort 2, along with listed terms and percentages. The record does not specify in this summary whether event terms overlap within participants, how the term percentages were calculated, or the relationship of these events to vedolizumab. It does not report causes or relationship assessments for the deaths. The adverse-event summaries cannot be treated as DLT results without an explicit connection to the endpoint criteria.

These limitations are specific to the information recorded: they do not establish that analyses or assessments were not performed, only that they are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose Finding Study of Vedolizumab for GvHD in Participants Undergoing Allogeneic HSCT — NCT02728895.
• Registry record last updated 2019-08-26; status last verified 2019-07.
• Results first posted 2019-08-26.
• 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

NCT02728895 is a completed, phase 1, open-label, non-randomized, parallel dose-finding study sponsored by Takeda. The study assessed intravenous vedolizumab alongside standard GvHD prophylaxis in participants undergoing allo-HSCT. Enrollment was 24. The recorded start date was 2016-06-15, and the primary completion date was 2018-07-10.

The dose groups listed were vedolizumab 75 mg, vedolizumab 300 mg, and a dose selected from the first two cohorts. Each cohort description specified dosing on Days -1, 13 and 42. The primary endpoint was the number of participants with DLTs from baseline up to Day 28, using the stated toxicity and engraftment criteria.

The registry record lists eight outcome measures and zero analyses. It does not report the primary DLT count, secondary outcome results, a statistical analysis plan, or the trial’s sample-size justification. Serious adverse-event summaries are listed for Cohort 1 and Cohort 2, but they are distinct from the unreported DLT endpoint.