Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation (NCT01665677), a non-randomized phase 2 study. The primary outcome is Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD)..

2. Clinical Question

The study asks whether atorvastatin, a medicine used to lower cholesterol, might be associated with reduced graft-versus-host disease after transplantation. The registry describes atorvastatin alongside standard prevention treatment, and its official title names micro-dose methotrexate and tacrolimus as well. However, the listed intervention is atorvastatin calcium; details about the delivery or contribution of each component are not reported in the registry record.

The primary question is narrower than the overall study rationale: it concerns grade II–IV acute graft-versus-host disease in matched related transplants, assessed at day 100. The endpoint is a participant count, not a reported treatment-effect estimate. Because the record classifies the study as nonrandomized and single-group, the listed donor groups should not be read as randomly assigned treatment and control groups. The registry record does not report a comparison that could isolate an atorvastatin effect from other differences between transplant recipients.

3. Trial Design

The registry identifies this as a phase II, nonrandomized, unmasked, single-group study, with enrollment of 69. Its status is completed. The study concerns atorvastatin as prophylaxis for acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. The brief summary describes daily oral atorvastatin beginning 14 days before transplant and continuing until 180 days after transplant, unless it is stopped earlier because of a bad side effect or severe graft-versus-host disease. The arm description gives a dose of 40 mg orally daily, starting on day -14 and continuing until +180 days; the text after “or” is not complete in the registry record.

The official title also names micro-dose methotrexate and tacrolimus administered only to transplant recipients. The brief summary says patients receive standard treatment to prevent graft-versus-host disease, while the listed intervention is atorvastatin calcium. The registry record does not provide enough detail to characterize the full prevention regimen beyond those descriptions.

Although the study is classified as single-group, its outcome and adverse-event information identifies matched related and unrelated donor groups. The primary endpoint is restricted to the matched sibling cohort; the description explicitly excludes matched unrelated donors from that analysis. The secondary outcomes concern chronic graft-versus-host disease in matched related and matched unrelated donor transplants. These donor categories are not described as randomized treatment arms. The record specifically cautions that this is not a like-for-like control comparison.

The primary endpoint timeframe is day 100. The registry does not report a protocol-level statistical plan, a sample-size justification, interim analyses, or a primary endpoint result. The enrollment figure describes the study record; it should not be treated as the denominator for the primary endpoint without an endpoint-specific population count.

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 Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD)., measured over Day 100.

The primary endpoint is the number of participants in the matched sibling cohort who develop grade II–IV acute graft-versus-host disease by day 100. It is recorded as a participant count. The registry says grading will follow consensus criteria and grading sheets suggested in the Bone Marrow Transplant Clinical Trials Network Manual of Procedures. It describes grade I as mild disease involving up to 25% of the skin; grade II as moderate disease involving 25 to 50% of the skin, with possible mild liver changes or mild diarrhea; grade III as severe disease involving over 50% of the skin, with liver involvement likely and stomach cramps and diarrhea possible; and grade IV as very severe disease, which may involve blistered or broken-down skin, yellow skin due to liver injury, and severe diarrhea.

Acute graft-versus-host disease is central to the study’s stated prevention question. Grouping grades II–IV focuses the endpoint on disease at least moderate in the registry’s grading description, rather than including grade I. The endpoint is also tied to a defined post-transplant assessment time, day 100. These choices make the outcome clinically interpretable as a count of participants meeting the specified severity threshold within that timeframe. They do not, by themselves, establish whether the count is high or low relative to an appropriate comparator.

The registry record does not report the observed count, the matched sibling cohort’s endpoint denominator, or an effect estimate. It therefore does not support a calculation of the proportion with the endpoint or a treatment comparison from this endpoint description alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a count of participants meeting a defined event criterion: grade II–IV acute graft-versus-host disease in the matched sibling cohort by day 100. A count answers how many participants experienced the event within the specified group and timeframe. To interpret the frequency of an event, readers also need the number of participants assessed in that group. The endpoint denominator is not reported in the registry record, and the study enrollment figure should not automatically be substituted for it.

In general, a count and a proportion answer different questions. A count records the number of observed events; a proportion relates that number to the relevant population at risk or assessed. A count without its matching denominator cannot establish the event frequency. A comparison between groups would additionally require a clear definition of each group, its population, and an appropriate analysis. The registry record does not report the primary endpoint count, denominator, or comparison estimate.

What does nonrandomized mean for interpretation?

In general, random assignment can help make comparison groups similar, on average, with respect to measured and unmeasured factors at the start of a study. In a nonrandomized study, group membership is not assigned by chance. Groups may therefore differ in ways that matter to outcomes. This is especially important when considering the matched related and unrelated donor categories: the registry does not describe them as randomized treatment groups and explicitly cautions that they are not a like-for-like control comparison.

For this study, the record classifies the design as single-group and nonrandomized. It is not appropriate to treat the unrelated donor group as a control for the matched related group simply because both appear in the record. Differences in donor category or other unreported characteristics could affect outcome patterns. Without an appropriate comparison design and analysis, a difference cannot be attributed to atorvastatin from these descriptions alone.

How should uncertainty be assessed?

In general, a confidence interval describes a range of values compatible with the data and the statistical model used. Its width conveys precision: a narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. A point estimate alone cannot show that precision. A p-value, when reported, describes how unusual data at least as extreme as those observed would be under a specified null model; it does not measure the size or clinical importance of an effect.

The registry record does not report a confidence interval, p-value, or other inferential analysis for the primary endpoint. It also does not report a model or an adjustment strategy. There is consequently no basis in the registry record for assessing the statistical uncertainty around the primary outcome or for interpreting statistical significance.

What is the role of the planning illustration?

The sample-size assumptions describe a planning illustration computed from an observed effect, not the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These are assumptions for illustrating planning scenarios, not evidence that the study used that allocation, that analysis, or those design choices. The trial itself is recorded as nonrandomized and single-group.

Sample-size planning illustrations are not observed power. In general, a planning calculation asks what sample size would be needed under chosen assumptions; it does not describe the uncertainty of an observed trial result. The registry record does not report the trial’s sample-size justification or a statistical plan showing that the illustration’s assumptions governed the study. The planning assumptions also do not supply the missing primary endpoint result.

Why do event definitions and timeframes matter?

Outcome interpretation depends on a prespecified event definition and observation period. Here, the record names the severity grades to be counted and sets the primary timeframe at day 100. Consistent grading criteria can make classification more reproducible, but the registry does not report how many events were observed, how many participants were evaluable, or whether any endpoint assessments were missing. These details are needed to understand the completeness and precision of the result.

In general, over-dispersion matters when count data vary more than an assumed statistical model expects. A model that does not account for that extra variation can understate uncertainty. The registry record does not report a count model, an over-dispersion assessment, or a model-based analysis for this endpoint. This is a general statistical consideration, not a claim that over-dispersion occurred in this study.

The registry lists zero analyses. This means the record does not provide a reported analysis entry from which to evaluate an estimate, its uncertainty, or the statistical procedure used. It does not justify inventing an analysis or treating the design assumptions for planning as the analysis actually performed.

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("Matched Related Donor")
n      <- c(30)
events <- c(3)
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  Matched Related Donor  30  3  10.0  2.1  26.5  3.5  25.6  3.6  25.8

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study evaluates several outcomes, comparisons, or timepoints. In general, testing many hypotheses can increase the chance of a false-positive finding if the analysis does not account for the number of tests. The registry lists a primary endpoint and secondary outcomes concerning grade II–IV chronic graft-versus-host disease in matched related and matched unrelated donor transplants. It does not report a multiplicity adjustment, a hierarchy for interpreting outcomes, or a statistical plan specifying how multiple tests would be handled. Whether any adjustment was used is not reported in the registry record.

The record does not provide a missing-data method, an account of endpoint completeness, or a description of how participants with unavailable assessments were handled. The primary endpoint description identifies the matched sibling cohort, but an endpoint-specific analysis population and denominator are not reported. Without these details, readers cannot determine whether the outcome count represents all eligible participants, only those with assessments, or another analysis population.

Analysis populations are important because the people enrolled, treated, followed, and included in a particular endpoint analysis may not be identical. The registry reports enrollment of 69, but it does not state the number included in the primary endpoint analysis. It also does not report whether participants who stopped atorvastatin early remained in an analysis population or how that circumstance affected outcome reporting.

The registry lists zero analyses and does not report interim analyses, missing-data handling, or the statistical plan. These omissions limit evaluation of selective outcome reporting and the robustness of any result. No claim about how multiplicity or missing data were handled can be made from 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: diarrhea (7.7%), sepsis (6.7%), lung infection (3.3%), bilirubin increased (3.3%), neutrophil count decreased (3.3%).

The registry’s serious adverse-event entries list 10 affected participants among 30 at risk in the Atorvastatin Calcium (Lipitor) group and 12 among 39 at risk in the Unrelated Donor group. The listed deaths are 0 in each group. Other adverse events are listed for 30 participants among 30 at risk in the Atorvastatin Calcium (Lipitor) group and 39 among 39 at risk in the Unrelated Donor group. These are registry group counts, not a randomized comparison of treatment and control.

The most frequently listed serious-event terms include diarrhea (7.7%) and sepsis (6.7%). Lung infection, bilirubin increased, neutrophil count decreased, and hyperglycemia are each listed at 3.3%. These percentages are reproduced as recorded; the registry does not give additional context about the event window, whether terms represent participants or episodes, or how events were attributed.

Serious adverse-event counts should not be read as proof that atorvastatin caused an event, nor do the counts establish that treatment prevented events. The registry does not explain whether the two groups had comparable safety follow-up or risk profiles. The unrelated donor group is not a like-for-like control comparison, as the record cautions. These entries describe reported safety information; they do not replace a comparative safety analysis.

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

The registry record establishes that a phase II study evaluated atorvastatin in the context of allogeneic hematopoietic cell transplantation and identifies grade II–IV acute graft-versus-host disease in matched related transplants by day 100 as the primary endpoint. It also records the study as completed and reports enrollment of 69. Those details describe the study’s registration and intended outcome; they do not provide an observed primary result.

The record does not report how many matched sibling participants developed the primary endpoint, the endpoint denominator, or an estimate of the event frequency. It therefore cannot establish from the posted results whether the observed outcome was more or less common than any benchmark or comparator. No confidence interval or p-value is reported for the primary endpoint, so its precision and statistical significance cannot be assessed.

The study’s nonrandomized, single-group classification is central to interpretation. The donor categories listed in the record are not a randomized control comparison, and the registry warns that the arms are not like-for-like. Even if group-specific outcomes were available, differences between these groups would not by themselves show that atorvastatin caused an outcome difference. A causal claim would require a suitable comparison and analysis, neither of which is reported in the record.

The safety entries show reported serious and other adverse-event counts, including zero deaths in the listed groups. They do not establish whether events were caused by atorvastatin, and the registry does not provide enough context to make a controlled safety comparison. The listed percentages for serious-event terms describe registry reporting, not treatment effects.

Accordingly, the record supports a description of the study design, intervention description, endpoint definition, and recorded safety entries. It does not support a conclusion about the efficacy of atorvastatin, the size or precision of an endpoint effect, or a causal safety assessment. Absence of a result in the registry record should not be treated as evidence that the outcome did or did not occur.

14. Why This Trial Matters Statistically

This study raises a practical statistical question: how should a proposed prevention strategy be evaluated when the record describes a nonrandomized, single-group study and also lists donor-defined cohorts? The design classification matters because a donor group is not automatically an adequate control. The registry itself cautions against treating its arms as like-for-like. That warning is essential for readers who might otherwise interpret group labels as evidence of a comparative treatment design.

The primary endpoint is also defined in a way that makes the target question clear. It is a count of matched sibling transplant recipients with grade II–IV acute graft-versus-host disease by day 100, assessed using named consensus grading criteria. Clear outcome definitions help readers understand what an event was intended to represent. At the same time, an endpoint definition cannot substitute for the result, denominator, and uncertainty estimate needed to interpret what happened.

Statistically, the record illustrates why trial status and enrollment alone are not enough to evaluate evidence. Although the study is completed and enrollment is recorded, the primary count, analysis population, statistical plan, and inferential results are not reported in the registry record. Without those elements, readers cannot assess the event frequency, precision, or robustness of the finding. The planning assumptions do not resolve these omissions: they are illustrations and not evidence of the study’s actual design or analysis.

The record is therefore useful for identifying the question and its limitations, rather than for estimating a treatment effect. Keeping those distinctions explicit helps prevent an endpoint description, a donor-group label, or safety counts from being mistaken for evidence of a causal benefit or harm.

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 primary limitation for interpreting this specific study is that the registry record does not report the primary endpoint result. It gives neither the matched sibling event count nor the endpoint denominator. As a result, readers cannot estimate the event frequency or its precision from the primary outcome description.

The design is recorded as both single-group and nonrandomized, while related and unrelated donor groups appear in the outcome and adverse-event information. The record explicitly says the arms are not a like-for-like control comparison. This structure limits what can be inferred from any between-group contrast and does not support attributing differences to atorvastatin. The record does not provide an adjusted comparison that might address group differences.

Details needed to evaluate conduct and analysis are not reported in the registry record. These include the statistical analysis plan, sample-size justification, analysis populations, missing-data handling, interim analyses, and multiplicity strategy. The record also does not describe endpoint completeness or the handling of participants who may have stopped atorvastatin early. The intervention description is incomplete at the end of the arm text, and the full contribution of the treatments named in the official title is not specified in the listed intervention.

The safety entries give group counts and serious-event terms, but the registry does not report enough context about timing, event attribution, or comparability of safety follow-up to support a causal safety interpretation. These limitations are specific to what is documented in the registry record; they do not establish what may have been reported elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation — NCT01665677.
• Registry record last updated 2023-05-15; status last verified 2023-04.
• Results first posted 2023-05-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes a completed phase II, nonrandomized, unmasked, single-group study of atorvastatin in allogeneic hematopoietic cell transplantation, with enrollment of 69. The primary endpoint is the number of participants in the matched sibling cohort with grade II–IV acute graft-versus-host disease by day 100. The record also lists chronic graft-versus-host disease outcomes for matched related and unrelated donor transplants.

The record describes daily atorvastatin beginning on day -14 and continuing until +180 days, with earlier discontinuation described for a bad side effect or severe graft-versus-host disease. It cautions that the donor groups are not a like-for-like control comparison. Serious adverse-event counts and terms are listed, but the primary endpoint result, endpoint denominator, and inferential analysis are not reported in the registry record.