Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment (NCT00079183), a na phase 2 study. The primary outcome is Number of Participants Experiencing Treatment Success.

2. Clinical Question

3. Trial Design

This completed phase II trial evaluated sirolimus as secondary therapy for chronic graft-versus-host disease that had not responded to prior treatment. The registry lists Fred Hutchinson Cancer Center as the sponsor, enrollment of 44, and the condition as graft-versus-host disease. The recorded start is 2002-04 and primary completion is 2009-07.

The design is single-group, with allocation recorded as not applicable and masking recorded as none. Participants received sirolimus once daily added to baseline prednisone plus either cyclosporine or tacrolimus, at the managing physician’s discretion. Because there was no separate comparator group, outcomes cannot be contrasted within this trial against outcomes under another assigned treatment.

The registry identifies the trial as phase II and lists a primary endpoint focused on treatment success. It also lists secondary outcomes concerning sirolimus discontinuation because of toxicity, infections by organism, secondary malignancies, prednisone treatment duration, survival, and recurrence of malignancy. The presence of these listed outcomes does not by itself establish which analyses were performed or what their results were.

The registry record lists 12 outcome measures and no analyses. It does not report details of the statistical analysis plan, eligibility criteria beyond the broad description of chronic disease not responding to prior treatment, or the reasons for choosing the enrollment target. It also does not describe an interim analysis plan. These omissions limit what can be concluded about how the trial was intended to handle estimation, uncertainty, or multiple outcomes.

The single-group structure is important for interpretation. Any observed outcome would describe the enrolled participants under the treatment approach used, but there is no concurrent randomized group in this record to separate treatment effects from other influences. Differences in baseline treatment, participant characteristics, disease course, or follow-up could matter when interpreting outcomes, but their distributions and effects are not reported.

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:

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: This includes all 44 consented subjects.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Experiencing Treatment Success, measured over Approximately 7 years.

The primary endpoint is the number of participants experiencing treatment success. The registry defines success using a combined clinical and treatment-status criterion: no immunosuppressive treatment, including sirolimus; resolution of all reversible manifestations of chronic graft-versus-host disease; and no additional systemic therapy. The stated timeframe is approximately 7 years.

This endpoint is used to represent a state that includes both disease manifestations and whether systemic immunosuppressive treatment is still being used. It is not simply a measure of whether sirolimus was started, whether an individual manifestation improved, or whether treatment was tolerated. A participant would have to meet all parts of the registry definition to count as a success under that definition.

The endpoint is recorded as a count of participants, so it is a binary outcome at the participant level: each participant either meets the defined success criterion or does not. A count alone does not show the proportion of the enrolled group meeting the criterion unless its denominator and analysis population are also specified. The registry record does not report the observed success count, the denominator used for an endpoint analysis, or an uncertainty interval. Consequently, the endpoint definition can be described, but the trial’s observed primary outcome cannot be quantified from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies a count of participants experiencing treatment success as the primary endpoint. Statistically, this is a binary participant-level outcome: the endpoint definition classifies a participant as meeting or not meeting the full success criterion. Counts are often accompanied by a denominator and a proportion, because a count alone depends on how many participants were actually included in that endpoint analysis. The registry record does not report the observed primary count, the analyzed denominator, or a proportion.

What does a single-group design allow?

A single-group study observes outcomes under the treatment approach used in the group. It can describe the number of participants who meet an endpoint and can assess the range of outcomes observed, if results are reported. It does not include a concurrently assigned comparator. Therefore, a single-group result cannot directly estimate a randomized between-group treatment contrast. Differences from outcomes in another population or from historical experience would require additional assumptions and information, which are not reported in the registry record.

In this trial, the treatment approach was sirolimus added once daily to baseline prednisone plus either cyclosporine or tacrolimus, chosen at the managing physician’s discretion. That discretion means the baseline combination was not described as assigned by random allocation. The record does not give the distribution of participants between the two baseline therapies or analyses by baseline regimen. Such details would matter when describing variation within the treated group, but cannot be inferred.

How should a count and an estimate be distinguished?

A count reports how many participants met a definition. A proportion relates that count to a specified denominator. An uncertainty interval around a proportion would convey how much statistical uncertainty remains about the underlying rate, given the observed data and a method. Those are different pieces of information, and none should be substituted for another. The registry’s enrollment figure does not establish the denominator for the primary endpoint: the record does not report how many participants had endpoint status assessed or how missing status was handled.

General statistical context: estimates from a small study can be imprecise, particularly for uncommon outcomes. The width of an uncertainty interval depends on the observed data and the analysis method. Because no primary estimate or interval is reported, the precision of the treatment-success outcome cannot be evaluated from the registry record. This general principle does not supply an estimate for this trial.

What is the role of the listed planning assumptions?

The record describes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It specifies that the effect to detect is a stated fraction of the observed effect, and distinguishes total events for time-to-event illustrations from participants per arm for other illustrations. These are planning assumptions, not a report of observed power and not a description of the actual single-group trial design. The numerical planning illustrations are not reported in the registry record.

A planning calculation asks what sample size a hypothetical study might require under specified assumptions. It does not show that a completed study had a particular probability of finding an effect, and it does not replace a treatment-effect estimate or its uncertainty. Here, the stated planning approach describes equal allocation between two arms, whereas the registered trial is single-group. The planning description should therefore not be read as evidence that this trial randomized participants or had a comparator arm.

Why does over-dispersion matter in general?

General statistical context: for count outcomes, a simple model may assume that variability follows a particular relationship to the average count. Over-dispersion occurs when the observed variability is greater than that assumption allows. If ignored, standard errors can be too small and uncertainty intervals can be too narrow. This issue is relevant to some count-data analyses, but the primary outcome is recorded as a count of participants meeting a binary criterion, and the registry record does not report a model or analysis addressing over-dispersion. It would be inappropriate to claim that a particular adjustment was used.

What can be learned from the listed adverse-event counts?

Adverse-event counts are descriptive unless an analysis specifies a comparison, a time period, and an appropriate denominator. A participant may experience more than one event, so counts of event types need not correspond to counts of affected participants. This is a general feature of adverse-event reporting, not evidence about how events were counted in this record. The registry provides at-risk and affected counts for serious and other adverse events, but does not report all event-level definitions, follow-up windows, or methods for attributing events to treatment.

The record also lists secondary outcomes that include survival and cumulative incidence outcomes. Such outcomes may require methods that account for timing and competing events. General statistical context: a competing event can prevent the event of interest from occurring, and treating it as ordinary loss to follow-up can give a misleading estimate. Although the listed outcomes include death without recurrent malignancy and recurrent malignancy, the registry record does not report the corresponding estimates or the methods used to calculate them.

The record lists no analyses. It consequently does not specify which statistical models, uncertainty measures, or hypothesis tests were used for the registered outcomes. Explanations of statistical concepts can clarify what would be needed to interpret such analyses, but cannot determine which methods were used in this trial.

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("Sirolimus")
n      <- c(44)
events <- c(8)
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  Sirolimus  44  8  18.2  8.2  32.7  9.5  32.0  9.6  32.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and no analyses. It identifies a primary endpoint and several secondary outcomes, including sirolimus discontinuation because of toxicity, infections categorized by organism, secondary malignancies, prednisone treatment duration, survival, and outcomes involving recurrent malignancy. The registry record does not report a multiplicity strategy, such as how interpretation of multiple outcome tests was intended to be controlled. It also does not report which of the listed outcomes were analyzed or whether any results were selected for reporting.

General statistical context: when many outcomes or hypotheses are examined, the chance of a seemingly notable result arising by chance can increase. A prespecified hierarchy, adjustment procedure, or clearly exploratory framing can help readers interpret multiple results. None of these approaches should be attributed to this trial because the analysis plan is not reported in the registry record.

Information about missing data and analysis populations is also not reported. The record does not state how participants with unavailable endpoint assessments were handled, whether all enrolled participants were included in each analysis, or whether the primary endpoint was analyzed among a defined subset. The enrollment figure alone does not answer these questions. For a participant-level endpoint, the number assessed and the handling of missing status affect the denominator and the interpretation of any count or proportion.

The approximate 7-year timeframe attached to the primary endpoint does not itself specify how follow-up was managed, when endpoint status was assessed, or how incomplete follow-up was handled. Those details are not reported in the registry record. Without them and without the outcome analysis, readers cannot assess the impact of missing observations or the consistency of follow-up across participants.

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: hospitalized for pneumonia (22.7%), hospitalized for renal insufficiency (9.1%), hospitalized for dehydration (6.8%), hospitalized for gvhd flare (6.8%), hospitalized for coag negative staph bacteremia (6.8%).

The registry lists 44 participants at risk for serious adverse events, with 22 affected, and 44 at risk for other adverse events, with 30 affected. It also reports 15 deaths. These are descriptive figures in a single-group study; the registry record does not provide a comparator group for judging relative event frequency. It does not report the causes or timing of the deaths, or establish that they were caused by sirolimus.

The serious adverse-event terms with listed percentages are hospitalized for pneumonia (22.7%), hospitalized for renal insufficiency (9.1%), hospitalized for dehydration (6.8%), hospitalized for GVHD flare (6.8%), hospitalized for Coag Negative Staph Bacteremia (6.8%), and hospitalized for Enterobacter Bacteremia (6.8%). The denominator and time window for these percentages are not reported in the registry record. These terms describe reported events; they should not be treated as a complete account of every event or as proof of treatment causation.

In general, participants can experience more than one event, so affected-participant counts and counts or percentages for individual event terms need not be mutually exclusive. The registry does not report enough detail to determine how the listed terms overlap. The percentages should therefore be read as the reported figures, without adding them together or treating them as separate groups.

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

The registry record establishes that a phase II, single-group trial evaluated sirolimus as secondary therapy for chronic graft-versus-host disease that had not responded to prior treatment. It also defines a primary treatment-success endpoint and lists descriptive safety figures. Those details describe the study’s scope, but they are not a report of the primary efficacy result.

The primary endpoint requires participants to be free of immunosuppressive treatment, including sirolimus, with resolution of all reversible manifestations and no additional systemic therapy. The registry gives an approximate 7-year timeframe but does not report the number of participants who met this definition. As a result, the record does not quantify the observed treatment-success outcome or its precision. It cannot support a numerical conclusion about the frequency of success.

The single-group design also limits causal interpretation. There is no randomized comparator to show what outcomes would have been under a different treatment approach. Even an observed change in a treated group would not by itself separate the contribution of sirolimus from other influences. This limitation is about the design, not a claim that the treatment had or did not have an effect.

The adverse-event figures provide counts of affected participants and listed serious-event terms, but do not establish that sirolimus caused those events. The registry does not report a comparison group, attribution details, or the timing and causes of the reported deaths. The safety data should be read as descriptive rather than as a comparative estimate of risk.

More broadly, a completed trial record and a defined endpoint do not guarantee that outcome estimates are available in the registry. In this record, no analyses are reported. The missing primary result, uncertainty measures, analysis population, and missing-data methods prevent a full statistical assessment of efficacy. These limitations do not erase the study’s descriptive information, but they set clear boundaries on what the record can establish.

14. Why This Trial Matters Statistically

This trial illustrates why design details and outcome reporting must be read together. Its primary endpoint is defined in clinical and treatment terms, combining resolution of reversible manifestations with discontinuation of immunosuppressive treatment and no additional systemic therapy. That definition is more informative than a broad label such as improvement, because it specifies what would count as success in the registry.

At the same time, the registry record does not report the number meeting the endpoint or any analysis. A precise endpoint definition cannot replace an observed result. Without the result, denominator, and uncertainty estimate, readers cannot assess the frequency of treatment success or the precision of an estimate.

The single-group design also makes the distinction between describing outcomes and estimating comparative effects especially important. The record documents sirolimus added to baseline therapy, but it does not provide a randomized comparison. Statistical interpretation must therefore avoid treating outcomes in this group as a controlled estimate of what sirolimus changed.

The record’s safety counts offer a further teaching point: participant-level counts, event terms, percentages, and deaths are different kinds of information. They need not have the same denominator or describe mutually exclusive categories. The registry does not report enough detail to resolve all of those relationships, so the figures should be read conservatively.

Finally, the record lists multiple outcomes but no analyses. This highlights the importance of reporting analysis populations, missing-data handling, multiplicity plans, and uncertainty alongside results. These details are not technical extras: they determine what a result represents and how strongly it can support an interpretation. The trial is statistically informative as an example of why endpoint definitions, design structure, and completeness of reporting all matter.

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 trial-specific limitations affect interpretation. The design is single-group, with no randomized comparator. Any reported outcome from such a design would describe the group treated in the study and would not provide a randomized comparison against another treatment strategy. The registry record does not report a comparative estimate.

The primary endpoint is defined, but its observed count is not reported. Nor are a denominator for endpoint assessment, an uncertainty interval, or an analysis population reported. The enrollment of 44 does not establish that all enrolled participants had endpoint status assessed. The registry record does not explain how missing endpoint information was handled.

The patient description is broad: chronic graft-versus-host disease not responding to prior treatment. The registry describes baseline prednisone plus either cyclosporine or tacrolimus at the managing physician’s discretion, but does not report the distribution of these regimens or outcomes by regimen. Additional details about eligibility and participant characteristics are not reported in the registry record.

The primary endpoint timeframe is approximately 7 years, but details about follow-up and endpoint ascertainment are not reported. The registry lists 12 outcome measures and no analyses, and does not report methods for multiplicity, missing data, or analysis populations. The adverse-event record includes affected counts, event terms, and deaths, but does not report the causes or timing of deaths, event attribution, or the denominator and time window for the listed percentages.

The trial is marked completed, but completion status alone does not provide missing outcome results or statistical methods. These limitations constrain interpretation of efficacy, safety, and precision; they do not establish that the study had any particular result.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment — NCT00079183.
• Registry record last updated 2017-06-20; status last verified 2017-05.
• Results first posted 2017-05-12.
• 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

NCT00079183 is a completed phase II, single-group study sponsored by Fred Hutchinson Cancer Center. It evaluated sirolimus added once daily to baseline prednisone plus either cyclosporine or tacrolimus for chronic graft-versus-host disease not responding to prior treatment. The registry records enrollment of 44, a start of 2002-04, and primary completion of 2009-07.

The primary endpoint is the number of participants meeting a treatment-success definition involving no immunosuppressive treatment, resolution of all reversible manifestations, and no additional systemic therapy, within an approximate 7-year timeframe. The observed primary result and analyses are not reported in the registry record. Descriptive safety information includes affected counts, listed serious-event terms, and deaths, but does not establish treatment causation or provide a randomized comparison.