Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts (NCT05005182), a non-randomized phase 2 study. The primary outcome is Erythroid Response Rate.

2. Clinical Question

3. Trial Design

This is a phase II study sponsored by Mayo Clinic. Its stated purpose is to study luspatercept with or without hydroxyurea in the specified myelodysplastic/myeloproliferative neoplasms with ring sideroblasts, with attention to safety, dosing and disease response. The registry lists the study as terminated. The recorded start date is 2023-02-20 and the primary completion date is 2023-04-17.

The design is parallel and non-randomized, with no masking. The registry describes a luspatercept cohort and a cohort receiving luspatercept with hydroxyurea. Without random assignment, the treatment groups are not guaranteed to be comparable at baseline. Consequently, a difference between their outcomes, if reported, could reflect differences in patient characteristics or other factors as well as treatment. The registry record does not report a randomized control group or a statistical adjustment that would address this limitation.

In the luspatercept regimen, patients receive luspatercept subcutaneously on day 1. In the combination regimen, luspatercept is given subcutaneously on day 1 and hydroxyurea orally on days 1-21. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. The study descriptions also include blood sample collection, bone marrow aspiration and biopsy, biospecimen collection, and questionnaire administration.

The registry reports enrollment of 3. The safety listings describe 1 participant at risk in the luspatercept cohort and 2 in the combination cohort. These figures are not a basis for assuming a comparative efficacy analysis. Although the record identifies six outcome measures, it lists no analyses. The protocol details, rationale for the enrollment target and statistical analysis plan 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

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: All patients have been combined in order to maintain patient privacy

6. Primary Endpoint

The registry lists the primary outcome as Erythroid Response Rate, measured over 8 weeks.

The primary endpoint is erythroid response rate, defined as the proportion of evaluable patients who achieve an erythroid response. The registry specifies an 8 weeks timeframe. Its denominator is not all enrolled patients by definition: evaluable patients are eligible patients who received at least one dose of study treatment. The record does not provide a response count, an evaluable-patient denominator or an observed response rate.

A proportion is a binary-outcome summary: each person is classified according to whether the defined event occurred, and the result describes the share meeting that definition. In general, this type of endpoint can express how often a response is observed in the population included in the analysis. Its interpretation depends on a clear response definition, consistent assessment and a transparent denominator. The registry description names erythroid response but does not give further response criteria in the posted endpoint information.

The endpoint is relevant to the study’s stated focus on disease response. It is not, on its own, a complete account of safety, durability or longer-term disease outcomes. The registry separately lists duration of response, time to leukemic transformation, leukemia-free survival, overall survival and adverse events as secondary outcomes. Results for those outcomes are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does an erythroid response proportion describe?

The primary outcome is binary at the participant level: a person either meets the erythroid response definition or does not. A response proportion describes the share of the endpoint’s analysis population that meets the definition. Here, the registry defines that population as eligible patients who received at least one dose of treatment on study, and gives 8 weeks as the assessment timeframe. The record does not report the count of responders or the number of evaluable patients, so no observed proportion can be interpreted from the registry information.

In general, a confidence interval around a proportion describes uncertainty about the underlying response frequency compatible with the observed data and the method used. It is not a guarantee that a future study will produce a value inside that interval. Precision depends on the amount of information in the analysis and the number of observed events. No confidence interval is reported for this primary endpoint in the registry record.

Why does the study design matter for a treatment contrast?

The study is described as parallel, non-randomized and unmasked. Parallel means that the treatment cohorts are followed as separate groups rather than participants switching through a sequence of regimens. Non-randomized allocation means assignment was not by random allocation as described in the record. In general, randomization helps balance measured and unmeasured prognostic factors between groups; without it, group differences may reflect patient selection or other baseline differences. Lack of masking can also affect assessment or reporting, depending on the outcome and study procedures. The registry does not report further measures to limit those risks.

Accordingly, a simple contrast between the cohorts would not by itself isolate a treatment effect. A reliable adjusted analysis would need a defined model and relevant covariates, as well as enough outcome information to support that analysis. No analysis is listed, and an adjustment strategy is not reported in the registry record. The cohorts should not be described as equivalent to randomized treatment and control arms.

How should sample-size planning be read?

The study record includes assumptions for planning illustrations: a two-sided significance level of 0.05, equal allocation between arms, a normal approximation and an effect to detect expressed as a stated fraction of the observed effect. These are assumptions for hypothetical planning, not evidence that the study had a particular chance of finding an effect. Sample-size illustrations are not observed power and do not substitute for an analysis of the trial data. The registry record does not report the study’s own sample-size justification or a statistical plan establishing that these assumptions were used to design the trial.

For a binary endpoint, planning generally depends on the response probabilities being compared, the chosen error threshold, allocation and the desired ability to detect a specified contrast. When an illustration uses a fraction of an observed effect, the resulting planning value depends on that effect estimate and should not be mistaken for a result from a new comparison. The registry record does not report an erythroid response estimate from which to assess such an illustration. Any displayed planning numbers should therefore be treated only as hypothetical design quantities, not as observed trial outcomes.

What does over-dispersion mean in general?

Over-dispersion is a general statistical issue that arises when observed variability is greater than a model expects. In studies with clustered, repeated or heterogeneous data, ignoring extra variability can make uncertainty appear smaller than it is. This trial record does not report an analysis using a count model or a finding of over-dispersion; the concept is not a reason to infer a particular method was used. For the primary binary endpoint, the key interpretive needs are the response definition, analysis denominator, estimate and uncertainty interval, none of which are fully reported as results.

What can the safety counts establish?

Safety listings are counts of participants with recorded events in the listed groups. They are not adjusted comparisons, and the record does not supply exposure-adjusted rates or a causal analysis. For serious adverse events, the luspatercept cohort lists 1 affected among 1 at risk, while the combination cohort lists 0 affected among 2 at risk. Other adverse events are listed for 1 among 1 at risk in the luspatercept cohort and 2 among 2 at risk in the combination cohort. These small denominators make percentages especially unstable; the counts should be read as descriptive observations within this study, not as estimates that can be generalized.

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 A (Luspatercept)", "Cohort B (Luspatercept, Hydroxyurea)")
n      <- c(1, 2)
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 A (Luspatercept)  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  Cohort B (Luspatercept, Hydroxyurea)  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including erythroid response rate, adverse events, duration of response, time to leukemic transformation, leukemia-free survival and overall survival. When a study examines several outcomes, the chance of at least one apparently notable result can increase if many statistical tests are performed. In general, multiplicity procedures can control that risk, but the appropriate approach depends on which outcomes are confirmatory and how the analyses are planned. The registry record does not report a multiplicity strategy or an analysis hierarchy.

The record lists no analyses, so it does not identify which endpoints were analyzed, which statistical tests were used or whether any adjustment for multiple testing was performed. It also does not report a statistical analysis plan. No inference should be made that multiplicity was addressed simply because one endpoint is labeled primary, nor that it was ignored; the approach is not reported in the registry record.

The primary endpoint definition describes the evaluable population as eligible patients who received at least one dose of treatment on study. This is a stated analysis-population definition, but the record does not report how many patients met it or how missing endpoint assessments were handled. Missing-data rules, treatment of participants without an assessment at 8 weeks, and any sensitivity analyses are not reported in the registry record. These details matter because the response proportion depends on who is included in its denominator and how incomplete outcome data are treated.

The registry’s enrollment and safety counts do not replace an endpoint-specific denominator. The efficacy population and response assessment results are not reported. Consequently, the primary endpoint cannot be reconstructed from the information recorded.

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: lung infection (100.0%).

The serious adverse event listings are descriptive counts. The luspatercept cohort lists 1 participant at risk and 1 with a serious adverse event; the luspatercept-plus-hydroxyurea cohort lists 2 at risk and 0 with a serious adverse event. The deaths field lists 1 for the luspatercept cohort and 0 for the combination cohort. The record does not establish that a death was caused by treatment or identify its relationship to an adverse event.

For other adverse events, the record lists 1 affected among 1 at risk in the luspatercept cohort and 2 affected among 2 at risk in the combination cohort. The serious-event terms include Lung infection at 100.0%. The denominator and calculation basis for that term percentage are not reported in the registry record, so it should not be interpreted as a risk estimate for all participants or as a comparison between regimens.

These group sizes are limited, and the counts do not provide a stable estimate of event frequency beyond the observed study participants. They also do not account for exposure time, event severity beyond the serious-event classification, or causal attribution. The figures describe what the registry lists, not comparative evidence of safety.

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

The registry record establishes that a phase II study was conducted with parallel, non-randomized cohorts receiving luspatercept alone or with hydroxyurea. It identifies erythroid response rate at 8 weeks as the primary endpoint, defines the evaluable population and records safety counts. It also lists secondary outcomes concerning response duration, leukemic transformation, survival and adverse events.

What it does not establish is the observed erythroid response rate. No primary response count, denominator, estimate or uncertainty interval is reported, and the registry lists no analyses. The outcome definition describes what the study intended to measure; it is not itself a result. The record therefore cannot show how common response was, how precise an estimate would be, or whether outcomes differed between treatment cohorts.

The safety counts are also limited to the listed participants and do not identify whether events were caused by study treatment. The record lists 1 serious adverse event in the luspatercept cohort and none in the combination cohort, along with the other event and death counts. These observations are too limited to support a broad comparative safety conclusion. The serious-event term listing does not resolve the missing context about its denominator or percentage basis.

Because allocation was non-randomized, a comparison between cohorts would not automatically represent the effect of adding hydroxyurea. The registry does not report an adjusted comparison or information sufficient to assess confounding. Termination is recorded, but its reason and implications for completion of assessments are not reported. These gaps limit what can be concluded from the registry record; they do not, by themselves, show that either regimen did or did not produce a particular outcome.

14. Why This Trial Matters Statistically

This study raises a useful statistical distinction between a question being specified and a result being available. The registry defines a primary binary endpoint and its assessment timeframe, but does not report the response data needed to estimate it. A clearly stated endpoint is necessary for interpretation, yet readers also need the numerator, denominator and uncertainty to understand what the study observed.

The design also illustrates why treatment-group labels do not make cohorts interchangeable with randomized arms. Non-randomized allocation can leave differences between groups that complicate treatment comparisons. This is particularly important when interpreting a small study: a few observations can strongly influence a proportion, while group imbalances may be difficult to evaluate. The registry lists enrollment of 3 and safety groups of 1 and 2 at risk, reinforcing that the posted counts should be read descriptively.

Finally, the record shows why status, outcome reporting and statistical planning are distinct. The study is marked terminated, but the reason is not reported. Planning assumptions do not substitute for an efficacy analysis, and the listing of secondary outcomes does not demonstrate that they were analyzed. The record is statistically informative about intended measurement and design limitations, while leaving the main response result unresolved.

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 available registry information leaves several trial-specific uncertainties. The study is marked terminated, but the reason for termination, whether enrollment and follow-up proceeded as planned, and whether all endpoint assessments were completed are not reported in the registry record. The listed primary completion date does not provide the missing response results or explain the status of each assessment.

The primary endpoint’s definition identifies eligible patients who received at least one dose as evaluable, but the number meeting that definition and the number assessed at 8 weeks are not reported. Further erythroid response criteria, handling of missing assessments and any sensitivity analyses are also not reported. Without those details, the endpoint estimate cannot be reproduced or checked.

The non-randomized allocation limits the interpretation of any between-cohort contrast. Baseline characteristics, reasons for treatment assignment and adjusted analyses are not reported in the registry record. No statistical analysis is listed, so the methods used for efficacy, safety or secondary outcomes cannot be assessed. The rationale for the enrollment target and the trial’s own sample-size justification are not reported.

The safety counts arise from small listed groups and are not accompanied by exposure-adjusted rates or causal attribution. The record does not give additional context for the Lung infection percentage, including its denominator. These limitations apply to interpretation of the registry record; they do not establish what unreported analyses or results may exist elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Luspatercept With or Without Hydroxyurea for the Treatment of Myelodysplastic/Myeloproliferative Neoplasms With Ring Sideroblasts and Thrombocytosis or Unclassifiable With Ring Sideroblasts — NCT05005182.
• Registry record last updated 2024-09-19; status last verified 2024-09.
• Results first posted 2024-09-19.
• 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

NCT05005182 is a Mayo Clinic phase II study of luspatercept with or without hydroxyurea for myelodysplastic/myeloproliferative neoplasms with ring sideroblasts. The study is listed as parallel, non-randomized and unmasked, with enrollment of 3 and status terminated.

The primary endpoint is erythroid response rate at 8 weeks among eligible patients who received at least one dose. The registry record lists no analyses and reports no primary response estimate. Safety listings record serious and other adverse events and deaths by cohort, but the small groups and missing analysis context limit interpretation. The reason for termination, missing-data procedures, multiplicity approach and statistical analysis plan are not reported in the registry record.