Tocilizumab for the Prevention of Graft Failure and GVHD in Haplo-Cord Transplantation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tocilizumab for the Prevention of Graft Failure and GVHD in Haplo-Cord Transplantation (NCT04395222), a non-randomized phase 2 study. The primary outcome is Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment.

2. Clinical Question

3. Trial Design

This is a prospective phase 2 study with non-randomized allocation, no masking and a sequential model. The registry record reports enrollment of 21 participants. Its status is active, not recruiting. The recorded study start is 2020-10-07, and primary completion is listed as 2022-09-28.

The study's stated purpose is to evaluate the safety of reducing and ultimately eliminating ATG from the haplo-cord transplant conditioning regimen and replacing it with tocilizumab. The stated aims include improving immune reconstitution and reducing relapse while preserving low rates of graft failure and graft-versus-host disease (GVHD). These are study aims, not reported findings.

Participants were assigned to sequential ATG Groups I through IV rather than randomized among concurrent arms. Group I, Group II and Group III descriptions specify progressively less ATG. Group IV's listed regimen contains no ATG, but the registry record says no participants were enrolled to that group because enrollment stopped before accrual reached the cohort. The arm descriptions are incomplete in the record, so details beyond the reported regimen text are not inferred.

Because allocation was non-randomized and sequential, differences between enrolled groups cannot be interpreted as if they arose from random assignment. Group membership may coincide with changes over the course of enrollment, and the groups may not be comparable on other factors. The registry record does not report a randomized comparator, masking, or a separate concurrent control arm.

Secondary outcomes listed include progression-free survival, overall survival, transplant-related mortality, platelet engraftment success, haplo-graft failure, acute GVHD and chronic GVHD. The record lists eight outcome measures, but it reports zero analyses. Results for these listed outcomes 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: No subjects were enrolled to ATG Group IV; study enrollment was stopped before accrual reached that cohort.

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: No subjects were enrolled to ATG Group IV; study enrollment was stopped before accrual reached that cohort.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Successful Haplo-derived Neutrophil Engraftment, measured over 21 days post-transplant.

The primary endpoint is the percentage of participants with successful haplo-derived neutrophil engraftment at 21 days post-transplant. The registry definition requires an absolute neutrophil count (ANC) of 500 cells/microL for three consecutive days, with the first qualifying day on or before Day +21 post-transplant. It also requires the absence of a second nadir after initial recovery, defined as a drop in ANC to <300 cells/microL for five consecutive days.

This endpoint captures both the timing and durability of early neutrophil recovery. Requiring consecutive days helps distinguish sustained recovery from a brief count increase, while the second-nadir criterion excludes recovery followed by a prolonged decline. As a general statistical concept, a clearly operationalized endpoint makes it more possible to classify participants consistently and to compare outcome proportions across study groups. The registry's definition provides those criteria, but does not report how many participants met them.

The stated timeframe is 21 days post-transplant. Group IV had no enrolled participants, so it cannot contribute observed primary endpoint data. The registry record also does not report a primary outcome percentage, uncertainty interval, or analysis. The endpoint definition alone therefore describes what was to be measured; it does not establish the observed frequency of successful engraftment or support a comparison between strategies.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary percentage represent?

A percentage of participants with an event is a binary-outcome summary: each participant either meets the stated endpoint definition or does not. For this trial, the event is successful haplo-derived neutrophil engraftment under the registry's timing, consecutive-day and second-nadir criteria. A percentage describes the observed proportion in a group, but its interpretation depends on how many participants were assessed and whether outcome status was available for them.

The registry record does not report the primary endpoint percentage or the analysis population used to calculate it. Without an observed proportion and its denominator, neither the event frequency nor its statistical precision can be assessed. An uncertainty interval, when reported, would describe a range of values reasonably compatible with the data under the chosen method. It would not by itself establish a causal effect or resolve limitations arising from the study design.

Why does allocation matter?

Randomization is a way to make treatment assignment independent of participant characteristics, on average, and supports a fair comparison between groups. This study is explicitly non-randomized and sequential. The cohorts were entered in stages, and ATG exposure changed across the described groups. A difference in outcome across those cohorts could reflect the regimen change, but it could also reflect other differences between participants or changes over time. A numerical contrast alone would not separate these explanations.

Masking is listed as none. In general, masking can reduce the influence of knowledge about assignment on care, assessment or reporting, depending on the outcome and setting. Neutrophil counts are objective measurements, but the registry record does not describe assessment procedures or whether any outcome adjudication occurred. Those details are not reported in the registry record.

How should precision be understood?

For binary outcomes, estimates based on small groups can be imprecise. General statistical reasoning says that fewer observations usually leave more uncertainty about the underlying event proportion, especially when events are uncommon or nearly universal. The observed group sizes are limited, and one enrolled group contains only one participant. This makes descriptive percentages particularly sensitive to the outcome of an individual participant. Group IV has no enrolled participants and therefore supplies no observed group estimate.

The registry record describes planning illustrations based on a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation and an effect set as a fraction of the observed effect. Such illustrations are planning calculations, not observed power. They do not establish that the study had a particular probability of detecting an effect, and they cannot compensate for the absence of a reported primary result. The record does not report the trial's own sample-size justification.

What do the safety counts convey?

The serious-event data give counts of participants at risk and affected in each group, along with death counts, and list serious-event terms with percentages. These are descriptive summaries. They do not provide a randomized comparison, adjustment for differences between groups, or an account of uncertainty around the estimates. A term percentage with a small or unclear denominator can look definitive while representing very few observations. The record does not report the term-specific denominators in the information available.

Over-dispersion is a general issue when event counts vary more across participants or groups than a simple statistical model expects. In that situation, a model that assumes less variability can produce uncertainty estimates that are too narrow. The registry record does not report a count model, an over-dispersion assessment or any inferential analysis of the adverse-event counts; these methods should not be assumed.

What analyses are reported?

The record lists eight outcome measures and zero analyses. It defines the primary endpoint and lists several secondary outcomes, but does not report estimates, confidence intervals, hypothesis tests or adjustment methods. The registry record does not report the statistical analysis plan, interim analyses, handling of missing outcome data, or analysis populations. These omissions prevent a detailed assessment of how the planned endpoint analyses were to be conducted and how uncertainty or multiple testing would have been handled.

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("ATG Group I", "ATG Group II", "ATG Group III")
n      <- c(10, 10, 1)
events <- c(8, 5, 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  ATG Group I  10  8  80.0  44.4  97.5  49.0  94.3  48.2  94.0
ARM  ATG Group II  10  5  50.0  18.7  81.3  23.7  76.3  23.4  76.6
ARM  ATG Group III  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists eight outcome measures, including the primary engraftment outcome and secondary outcomes covering survival, transplant-related mortality, platelet engraftment, graft failure and GVHD. It reports zero analyses. No outcome estimates, hypothesis tests or confidence intervals are reported, so the number of analyses actually performed cannot be inferred from the listed outcomes.

When several outcomes are assessed, the chance of at least one apparently notable finding can increase if each is tested separately. General statistical approaches to multiplicity include designating a primary outcome in advance, adjusting significance thresholds, or treating secondary results as exploratory. The registry record does not report a multiplicity strategy or the prespecified hierarchy, if any, beyond identifying the primary outcome.

The record does not report how missing outcome data were handled, what constituted the analysis population, whether all enrolled participants were assessed for each outcome, or how deaths and other events affected endpoint evaluation. These details matter because exclusion or incomplete assessment can change the denominator and potentially bias a percentage. They are not reported in the registry record.

Thus, the endpoint definitions and outcome list identify what the study intended to assess, but not how missingness or multiple outcomes were addressed in analysis. No inferential interpretation should be drawn from unreported tests or assumed analysis procedures.

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: acute graft-versus-host disease (100.0%), delayed engraftment (100.0%), hypovolemic shock (100.0%), septic shock (100.0%), bacteremia (20.0%).

The registry reports serious-event information by ATG group, including counts at risk, counts affected and deaths. In Group I, 8 participants are listed as affected among 10 at risk; Group II lists 9 affected among 10 at risk; Group III lists 1 affected among 1 at risk; Group IV lists 0 at risk and 0 affected. Death counts are listed as 5, 1, 1 and 0, respectively. These are descriptive registry counts and should not be treated as comparative risk estimates.

The serious-event terms include Acute Graft-versus-Host Disease, Delayed Engraftment, Hypovolemic shock and Septic Shock, each listed as 100.0%. Bacteremia and Diarrhea are each listed as 20.0%. The information reported does not specify the denominator behind each term percentage, so the percentages cannot be interpreted as group-wide rates from the record alone. The percentages also do not show whether events were judged related to a particular intervention.

The cohorts are non-randomized and sequential, and their sizes differ substantially. Group III has one participant, and Group IV has none. These counts do not establish that one regimen caused more or fewer serious events than another, and the record does not report comparative safety analyses or uncertainty intervals.

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

The registry record establishes that this was a prospective phase 2 study of a sequential strategy to reduce ATG and ultimately eliminate it from haplo-cord transplant conditioning, with tocilizumab part of the study strategy. It also provides a precise primary outcome definition: sustained neutrophil recovery within the stated timeframe without the specified second nadir. These design details clarify what the study set out to evaluate.

They do not establish the primary endpoint result. The registry record does not report the number or percentage of participants with successful engraftment, an uncertainty interval, or an analysis. It also reports no analyses for the listed secondary outcomes. Accordingly, the record does not demonstrate the frequency of engraftment, whether outcomes differed across the ATG groups, or whether the study aims regarding immune reconstitution, relapse, graft failure or GVHD were met.

The absence of enrollment in Group IV is especially important for interpretation. Although Group IV represents the planned ATG-free cohort, there are no participants from whom to estimate outcomes for that group. The record therefore cannot establish outcomes under the planned ATG-free regimen.

General statistical interpretation distinguishes an observed description from a causal comparison. Even if group-specific outcome estimates were available, sequential non-randomized allocation would limit conclusions about whether a difference was caused by regimen changes. Participant differences, time-related changes or other factors could also contribute. The available serious-event counts are descriptive and do not resolve those concerns.

These limitations do not erase the value of the endpoint definition or the descriptive information recorded. They do mean that conclusions should be confined to the study's design, its stated aims, the reported enrollment and safety counts, and the fact that the primary result and analyses are not reported in the registry record.

14. Why This Trial Matters Statistically

This study raises a statistical question common in early clinical research: how to evaluate a staged change in a treatment strategy when cohorts are small and assignment is not randomized. The sequential design makes the progression in ATG exposure central to the question, but it also means that differences between cohorts cannot be interpreted as clean treatment contrasts.

The primary endpoint is defined with explicit biological criteria and a time boundary. That level of detail matters because binary outcomes depend on consistent classification. The additional requirement that recovery not be followed by a second nadir makes the endpoint about sustained recovery rather than a single count threshold alone. However, a well-defined endpoint cannot substitute for an observed result and an account of its precision.

The incomplete accrual of the planned ATG-free cohort is also statistically consequential. Without participants in Group IV, no group-specific outcome estimate can describe that stage of the strategy. This leaves a gap between the study's stated intended progression and the enrollment actually recorded.

Finally, the record illustrates why safety percentages need denominators and context. A percentage alone does not convey how many participants contributed, how uncertain the estimate is, or whether the groups are comparable. Reporting of analysis methods, missing-data handling and outcome results is needed to move from an outcome definition and event counts to an interpretable statistical assessment.

The trial matters statistically as an example of the distinction between a planned evaluation and evidence reported in a registry. Its design and endpoint can be described, but the absent analyses and primary result place a firm limit on what can be concluded from the record.

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 registry information for this study. The primary outcome is defined, but the registry record does not report its observed result, denominator, uncertainty interval or statistical analysis. The record lists eight outcome measures but zero analyses, leaving the listed clinical aims without reported analytic results.

The study is non-randomized, unmasked and sequential. These features limit direct comparisons among the ATG groups because assignment was not random and group membership followed stages of the study. The registry record does not report baseline characteristics or adjusted comparisons that could help assess group comparability.

Enrollment was 21, and no participants entered Group IV, the planned ATG-free cohort. Group III included one participant. Estimates from small cohorts would be highly sensitive to individual outcomes, while no estimate is possible for a group with no enrolled participants.

The serious-event summary lists affected counts and term percentages, but the registry information does not report the denominator for each serious-event term percentage, the methods used to classify events, or comparative safety analyses. It also does not report missing-data procedures, analysis populations, multiplicity handling, interim analyses, or the trial's own sample-size justification. These details are not reported in the registry record and should not be inferred from the design description.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Tocilizumab for the Prevention of Graft Failure and GVHD in Haplo-Cord Transplantation — NCT04395222.
• Registry record last updated 2026-01-06; status last verified 2025-12.
• Results first posted 2023-10-23.
• 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 prospective phase 2 study evaluates a sequential strategy to reduce and ultimately eliminate ATG in haplo-cord transplant conditioning, replacing it with tocilizumab. The registry reports non-randomized allocation, no masking, enrollment of 21 and active, not recruiting status.

The primary endpoint is successful haplo-derived neutrophil engraftment by 21 days post-transplant, defined by sustained ANC recovery without the specified second nadir. No participants enrolled to ATG Group IV. The registry lists eight outcome measures and zero analyses; the primary endpoint result is not reported in the registry record.

Serious-event counts are descriptive, and the sequential non-randomized design does not support like-for-like causal comparisons between groups. The record does not report the statistical analysis plan, missing-data methods or multiplicity approach.