Clofarabine for Myelodysplastic Syndrome (MDS) Patients Who Failed Vidaza Treatment (tx): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clofarabine for Myelodysplastic Syndrome (MDS) Patients Who Failed Vidaza Treatment (tx) (NCT00700011), a non-randomized phase 2 study. The primary outcome is Improvement in Peripheral Blood Count and Reduction in Number of Transfusions.

2. Clinical Question

The study was framed as an investigation of clinical and laboratory effects of clofarabine after failure of 5-azacytidine. The investigators also hypothesized that clofarabine might induce DNA hypomethylation, in addition to its described effects on DNA synthesis and repair and apoptosis. These are study rationales and hypotheses, not outcome findings. A secondary outcome listed the number of participants with DNA hypomethylation during the study, but its results are not reported in the registry record.

3. Trial Design

This was a phase 2, non-randomized, unmasked, single-group study with two clofarabine dose cohorts. The registry reports enrollment of 10 participants and identifies myelodysplastic syndromes as the condition studied. The official study title describes an intravenous clofarabine pilot study. The registry lists Texas Oncology Cancer Center as sponsor.

The study description specifies two dose schedules: clofarabine 10 mg/m2 daily for five days per cycle in the first cohort, and 5 mg/m2 daily for five days per cycle in the second. The arm descriptions say cycles were intended to occur every 28 days but could be delayed to allow bone marrow recovery. The brief summary describes the schedule as every four to six weeks. Both arm descriptions state that Neulasta was given on day 5 of each cycle.

Because allocation was non-randomized and there was no separate control group, the cohorts do not establish a randomized dose comparison. The record does not report how participants were assigned to dose, whether assignment followed a fixed sequence, or whether other design features were intended to make the cohorts comparable. Those details are not reported in the registry record.

The study began in 2008-03 and had a primary completion date of 2010-03. Its status is terminated. The reason for termination and whether termination was related to recruitment, safety, efficacy, or another consideration are not reported in the registry record. A terminated status alone does not indicate what the clinical outcomes were.

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: There were no screen fails due to pre-screening thoroughly. The plan was to sign eight patients to the 10 mg/m2 arm and then eight to the 5 mg/m2 arm, but recuitment was difficult and decision was made to close study in early 2010, so only two patients were assigned to 5 mg/m2 arm.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients considered for analysis except for one on the 5 mg/m2 arm who died within 2 weeks after cycle one making this unassessable for that patient.

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 Improvement in Peripheral Blood Count and Reduction in Number of Transfusions, measured over 2-3 months.

The primary outcome was titled Improvement in Peripheral Blood Count and Reduction in Number of Transfusions. It was measured as a number of participants and had a registry timeframe of 2-3 months. The description defines hematologic improvement using an increase in hemoglobin of 1.5 g/dL or a reduction in the need for PRBC transfusions by at least 4 units over an 8 week period. It also lists an increase of at least 100% and an ANC of >0.5 x 10^9/L, and platelet-count criteria: an increase of >30 x 10^9/L for patients starting at > 20 x 10^9/L, or an increase from <20 x 10^9/L to >20 x 10^9/L and by at least 100%.

The registry wording lists several blood-count and transfusion criteria, but does not fully specify how the criteria are combined into one participant-level classification. That operational detail is not reported in the registry record. The primary outcome population includes all patients considered for analysis except one participant in the 5 mg/m2 arm who died within 2 weeks after cycle one, making the outcome unassessable for that participant.

General rationale: blood counts and transfusion requirements can describe hematologic changes in terms that are interpretable for a population with myelodysplastic syndrome. A participant count meeting a prespecified improvement definition can summarize how often the defined response occurred. However, no primary outcome count or response estimate is reported in the registry record, so the posted information does not establish how often improvement occurred.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome was planned? The primary endpoint is a binary participant-level outcome: a participant either meets the stated hematologic-improvement definition or does not. The registry expresses the result as a number of participants. General statistical explanation: for a binary endpoint, a response proportion is often used to describe the share of an analyzed group meeting the definition. The proportion and its uncertainty depend on the number assessed and the number classified as having the outcome. The registry record does not report those primary outcome counts or a calculated proportion.

Why does the study design matter? The study is identified as non-randomized, unmasked, and single-group, while its description includes two dose cohorts. The record does not describe random assignment, and it does not identify a separate control arm. General statistical explanation: random allocation helps balance known and unknown prognostic factors on average across groups. Without it, outcome differences between cohorts can reflect differences in who entered each cohort, in addition to any effect of dose. A statistical adjustment can sometimes address measured differences, but the adjustment approach is not reported in the registry record. Even an adjusted analysis cannot automatically eliminate bias from unmeasured differences.

What would an uncertainty interval mean? General statistical explanation: a confidence interval describes the range of estimates reasonably compatible with the observed data under the assumptions of the method. For a binary response, it would communicate the precision of an estimated response proportion or contrast. With small groups, estimates can be especially imprecise, and the interval is important alongside the point estimate. No primary outcome confidence interval is reported in the registry record. The absence of an interval does not mean the result was precise; it means that precision cannot be assessed from the posted primary outcome information.

What can a hypothesis test establish? General statistical explanation: a p-value assesses how compatible data are with a specified null model, given the analysis assumptions. It is not the probability that a treatment works, nor does it describe the size or clinical importance of an effect. For this study, the registry lists 0 analyses. No primary endpoint p-value or statistical comparison is reported. The statistical analysis plan, including any model or test intended for the primary outcome, is not reported in the registry record.

How should sample-size calculations be read? The record describes planning illustrations based on the observed effect, using 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 planning illustrations rather than the study's own design justification, and they are not observed power. The registry does not report a sample-size justification for the trial. A planning calculation does not demonstrate that the study had a particular probability of finding a result, and it cannot replace an estimate and uncertainty interval from the actual observed outcome data.

Why does over-dispersion matter in general? General statistical explanation: over-dispersion occurs when observed variability is greater than expected under a model's assumptions. If a method assumes less variability than the data contain, standard errors and uncertainty intervals may be too small, and hypothesis tests may appear more decisive than warranted. A binary participant outcome is not itself a count-rate endpoint requiring a dispersion parameter, and the registry does not report a model assessing over-dispersion for the primary outcome. No claim about over-dispersion in this study can therefore be made from the record.

What is the role of analysis populations? General statistical explanation: an analysis population specifies which participants contribute to a particular endpoint analysis. It is important to distinguish enrollment, treatment exposure, and endpoint assessability, because they need not be identical. The registry's primary outcome population note excludes one 5 mg/m2 participant from assessment after death within 2 weeks after cycle one. The record does not give a complete accounting of endpoint assessment for every participant or explain any other exclusions. The adverse-event risk denominators are 8 and 2, but the registry does not explain their relationship to all other analysis populations.

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("10 mg/m2 Group", "5 mg/m2 Group")
n      <- c(8, 1)
events <- c(3, 1)
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  10 mg/m2 Group  8  3  37.5  8.5  75.5  13.7  69.4  13.7  70.1
ARM  5 mg/m2 Group  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures and 0 analyses. It identifies the primary hematologic-improvement outcome and lists a secondary outcome concerning the number of participants with DNA hypomethylation during the study. Results for the primary outcome and the secondary laboratory outcome are not reported in the registry record.

A multiplicity plan describes how interpretation is handled when a study evaluates multiple outcomes, time points, groups, or statistical tests. General statistical explanation: testing many hypotheses can increase the chance of at least one apparently unusual result, so a prespecified approach helps distinguish primary confirmatory questions from exploratory analyses. The registry record does not report whether multiplicity was addressed, whether any outcome hierarchy was specified, or whether interim analyses were planned. The analysis plan and any interim-analysis details are not reported in the registry record.

The primary outcome population note identifies one participant in the 5 mg/m2 group who died within 2 weeks after cycle one, making assessment of that endpoint impossible for that participant. The record does not describe how this unassessable outcome was handled in an analysis, or how other missing or unavailable outcome data were handled. No broader missing-data method is reported.

The registry does not report a complete analysis-population definition beyond the primary outcome note. It is therefore not possible to determine from the posted information whether all enrolled participants were included in every outcome analysis or how denominators were set for outcomes other than the safety counts. These omissions limit reproducibility and make it difficult to compare any potential estimates across outcomes or cohorts.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: thrombocytopenia (100.0%), infection w/ a grade 3-4 anc (50.0%), pneumonia (12.5%), infection w/ normal anc (12.5%), hemorrhage - nosebleed (12.5%).

The adverse-event record gives counts by dose group. Serious adverse events were reported for 6 of 8 participants at risk in the 10 mg/m2 group and 2 of 2 in the 5 mg/m2 group. Other adverse events were reported for 8 of 8 and 2 of 2 participants, respectively. These are counts within the registry's stated risk groups; they do not establish a causal effect of clofarabine or a comparative safety difference between doses.

The registry lists thrombocytopenia at 100.0% and infection with a Grade 3-4 ANC at 50.0% among the top serious terms. Pneumonia, infection with normal ANC, nosebleed hemorrhage, and dehydration are each listed at 12.5%. The record does not give further event-level details in the information described, such as timing, duration, recurrence, or severity beyond the term wording. The percentages should be read as the registry's reported figures, not as rates recalculated from the group counts.

The dose cohorts are non-randomized and small, with different numbers at risk. Comparisons of their serious-event counts or percentages therefore require caution. Group-specific death counts in the adverse-event information are not reported in the registry record. Separately, the primary outcome population note reports that one participant in the 5 mg/m2 group died within 2 weeks after cycle one.

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

The record describes a pilot phase 2 study examining clofarabine at two dose levels in patients with myelodysplastic syndrome after failure of 5-azacytidine. Its primary endpoint was framed around hematologic improvement, including blood-count changes and reduced transfusion requirements. This makes the question clinically focused, but the registry does not report the primary outcome results. The frequency of improvement and its precision therefore cannot be characterized from the posted information.

The study description also raises a laboratory hypothesis about DNA hypomethylation. A hypothesis is a proposed explanation to be evaluated, not evidence that the proposed mechanism occurred. Although the registry lists DNA hypomethylation as a secondary outcome, it does not report its result. The record consequently cannot show whether the laboratory outcome was observed or whether it was related to hematologic changes.

The two dose cohorts do not provide a randomized dose comparison. Non-randomized allocation means that observed cohort differences, if available, could reflect differences in participants or other factors rather than dose alone. The registry's safety counts also should not be read as evidence that one dose is safer or less safe than the other: the groups are not randomized, and their numbers at risk differ.

The terminated status is a feature of the registry record, but the reason for termination is not reported. It does not, by itself, establish that the study stopped because of benefit, lack of benefit, harm, recruitment difficulty, or another cause. The listed safety events provide descriptive information, but they do not supply a complete evaluation of risk or a comparative treatment effect.

Overall, this record documents the study question, design, outcome definitions, and some adverse-event counts. It does not report the efficacy outcome values, the laboratory outcome result, or inferential analyses. It therefore does not support a numerical estimate of clofarabine's effect in this study or a conclusion about the relative performance of the two dose cohorts.

14. Why This Trial Matters Statistically

This study illustrates why the distinction between a treatment cohort and a control group matters. Two dose levels can appear to create a direct comparison, but non-random allocation does not ensure comparable groups. A numerical difference between cohorts would be descriptive unless the design and analysis adequately addressed possible differences between participants. The registry identifies the study as non-randomized and single-group, so it should not be interpreted as a randomized dose trial.

It also illustrates the importance of outcome reporting. The primary endpoint is described in detail, including blood-count and transfusion criteria and a timeframe, yet no primary outcome result is reported. Without the number meeting the endpoint and the number assessed, readers cannot estimate the response frequency or judge its precision. A detailed endpoint definition is useful, but it cannot substitute for the result itself.

The primary outcome note about one unassessable participant shows why analysis populations and missing outcome handling matter. Enrollment alone does not explain who contributed to each endpoint. Clear reporting should identify the analysis denominator and describe how unavailable outcomes were handled. Those details are not fully reported in the registry record.

Finally, the safety information demonstrates the limits of reading group percentages without design context. The groups differ in size and were not randomized; their event summaries do not establish comparative safety. The record gives descriptive counts and selected serious-event terms, while leaving the primary efficacy results, secondary laboratory result, and several analysis details unreported. These are statistical limitations on what can be inferred, regardless of the biological rationale motivating the study.

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.

This trial's non-randomized design limits causal interpretation of any difference between the 10 mg/m2 and 5 mg/m2 cohorts. The registry does not describe the dose-assignment process, so the extent to which participants differed at baseline cannot be assessed from this record. There is no randomized control group, and the dose cohorts should not be treated as equivalent to a treatment-versus-control comparison.

The registry reports enrollment of 10, while the safety groups list 8 and 2 participants at risk. The primary outcome population note separately identifies one participant in the 5 mg/m2 group as unassessable after death within 2 weeks after cycle one. The record does not provide a complete flow of participants through treatment and endpoint assessment, or explain whether other outcomes had different analysis populations.

The primary endpoint description includes several blood-count and transfusion criteria, but the exact logical combination for classifying improvement is not fully specified in the wording. No primary outcome counts, estimates, or uncertainty measures are reported. The secondary DNA hypomethylation outcome is also listed without a result. Consequently, neither clinical outcome magnitude nor laboratory outcome occurrence can be evaluated using the registry information.

The study is marked terminated, but the reason is not reported. The registry record also does not report the statistical analysis plan, multiplicity handling, missing-data methods, interim analyses, or a trial-specific sample-size justification. These gaps constrain interpretation of the outcome definitions, analysis choices, and study completion. They do not establish why the record is incomplete or why the study was terminated.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clofarabine for Myelodysplastic Syndrome (MDS) Patients Who Failed Vidaza Treatment (tx) — NCT00700011.
• Registry record last updated 2013-03-15; status last verified 2013-03.
• Results first posted 2013-01-09.
• 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 is a phase 2, non-randomized, unmasked, single-group study of intravenous clofarabine for myelodysplastic syndrome after failure of 5-azacytidine. The study description includes dose cohorts of 10 mg/m2 and 5 mg/m2, each given daily for five days per cycle. The registry reports enrollment of 10, sponsor Texas Oncology Cancer Center, a start date of 2008-03, a primary completion date of 2010-03, and terminated status.

The primary outcome concerns hematologic improvement based on peripheral blood counts and transfusion requirements, with a timeframe of 2-3 months. One participant in the 5 mg/m2 group was unassessable for that outcome after death within 2 weeks after cycle one. The registry also lists DNA hypomethylation as a secondary outcome. Primary and secondary outcome results, statistical analyses, and the reason for termination are not reported in the registry record.

Safety counts are reported for 8 participants at risk in the 10 mg/m2 group and 2 in the 5 mg/m2 group. Because allocation was non-randomized and no randomized control group is listed, the cohorts do not support a like-for-like treatment comparison.