A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I) (NCT00317642), a randomized phase 3 study. The primary outcome is Overall Survival - Overall and by Calculated Strata (CSR 7-April-11).

2. Clinical Question

3. Trial Design

The registry describes a Phase III, randomized, double-blind, controlled, parallel-group study. It records enrollment of 326 and a completed status. The study start is recorded as 2006-08, and primary completion as 2012-01. The sponsor is Genzyme, a Sanofi Company.

Participants were assigned to clofarabine plus cytarabine or placebo plus cytarabine. The combination arm used intravenous clofarabine followed by cytarabine; the control arm used placebo followed by cytarabine. Participants could receive up to 3 cycles, including induction, re-induction, and consolidation. The registry describes randomization as stratified by remission status following the first induction regimen: no remission or remission less than 6 months, compared with remission at least 6 months. It defines CR1 as remission after the first pre-study induction regimen.

The primary endpoint was overall survival in the Full Analysis Set. This population is described as randomized participants whose baseline AML diagnosis was centrally confirmed. The primary outcome timeframe is from Day 1, defined as randomization, up to approximately 4 years. Analyses by calculated strata used remission-duration information from case report forms and did not include IVRS mistakes. The registry notes that one participant in the placebo group could not be assigned a stratum in that description. The full details of this participant's handling are not reported in the registry record.

The arm descriptions, outcome populations, and analysis strata should be read as reported rather than assumed to be interchangeable. In particular, the calculated strata are distinguished from the randomized strata in some outcome titles. Further details on the masking roles, allocation procedures, protocol deviations, and complete statistical 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.

Before assignment: 352 patients screened and 326 randomized, 163 to each treatment group. One participant withdrew after being randomized to the Placebo and Cytarabine Group and was excluded from efficacy analysis.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS)-all randomized participants whose baseline AML diagnosis was centrally confirmed. Strata are calculated according to duration of the first remission based on case report forms (CRF) data and do not include the IVRS mistakes. One participant's strata (placebo group) could not be calculated so the participant was excluded.

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 Overall Survival - Overall and by Calculated Strata (CSR 7-April-11), measured over Day 1 (randomization) up to approximately 4 years.

Overall survival measures the time from randomization until death from any cause. The registry reports this outcome from Day 1 up to approximately 4 years, in the Full Analysis Set. It gives the median time in each group and a 95% confidence interval, along with the sponsor-reported hazard ratio and Log Rank test.

Overall survival is a time-to-event endpoint: the analysis uses both the timing of deaths and the information from participants whose follow-up ends before a recorded death. A median is the estimated time by which half of the relevant group has experienced the event, subject to the analysis and follow-up data. It is not the average survival time, nor does it state how long any particular participant lived.

Death from any cause is a clearly defined event that does not require classifying the cause of death as related to AML or study treatment. This can make the endpoint useful for an overall comparison of the randomized groups. At the same time, overall survival does not identify the pathway behind a group difference. It does not, on its own, describe remission, disease progression, treatment tolerability, or the balance of benefits and harms. Those questions require other outcomes and careful interpretation of their analysis populations and uncertainty.

The registry's definition specifies the event and the time origin, but further operational details about censoring and follow-up are not reported in the registry record. The reported estimates should therefore be interpreted within the limits of the information recorded for this endpoint.

7. Results Posted in the Registry

• Clofarabine (IV Formulation) and Cytarabine (FAS) vs Placebo and Cytarabine (FAS): hazard ratio 1.00 (95% CI 0.78–1.28), reported p = 0.995 (as reported in the registry).
• Clofarabine and Cytarabine - In Stratum < 6 Months vs Placebo and Cytarabine - In Stratum < 6 Months: hazard ratio 1.13 (95% CI 0.81–1.57), reported p = 0.467 (as reported in the registry).
• Clofarabine and Cytarabine In Stratum >= 6 Months vs Placebo and Cytarabine In Stratum >= 6 Months: hazard ratio 0.85 (95% CI 0.58–1.24), reported p = 0.396 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Clofarabine (IV Formulation) and Cytarabine vs Placebo and Cytarabine: hazard ratio 0.63 (95% CI 0.49–0.80), reported p < 0.001 (as reported in the registry).
  • Clofarabine and Cytarabine - In Stratum < 6 Months vs Placebo and Cytarabine - In Stratum < 6 Months: hazard ratio 0.67 (95% CI 0.49–0.93), reported p = 0.013 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically lower for Clofarabine (IV Formulation) and Cytarabine vs Placebo and Cytarabine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically lower for Clofarabine and Cytarabine - In Stratum < 6 Months vs Placebo and Cytarabine - In Stratum < 6 Months than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Clofarabine (IV Formulation) and Cytarabine vs Placebo and Cytarabine: hazard ratio 0.63 (95% CI 0.49–0.79), reported p < 0.001 (as reported in the registry).
  • Clofarabine and Cytarabine - In Stratum < 6 Months vs Placebo and Cytarabine - In Stratum < 6 Months: hazard ratio 0.73 (95% CI 0.53–1.01), reported p = 0.049 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval excludes no difference (a ratio of 1), so the hazard of the event is statistically lower for Clofarabine (IV Formulation) and Cytarabine vs Placebo and Cytarabine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Clofarabine and Cytarabine - In Stratum < 6 Months vs Placebo and Cytarabine - In Stratum < 6 Months and the control. The interval gives the range of effects that remain compatible with the data.

Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Clofarabine (IV Formulation) and Cytarabine: 37.7% (61/162) versus 16.6% (26/157) on control; risk difference 21.1 percentage points (95% CI 11.6 to 30.6), risk ratio 2.27 (1.52–3.40); unadjusted two-proportion z-test p = <0.001.
  • Clofarabine and Cytarabine - In Stratum < 6 Months: 35.2% (31/88) versus 16.6% (26/157) on control; risk difference 18.7 percentage points (95% CI 7.1 to 30.2), risk ratio 2.13 (1.35–3.34); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Clofarabine (IV Formulation) and Cytarabine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Clofarabine and Cytarabine - In Stratum < 6 Months than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broaden the statistical picture beyond overall survival. They include response, duration of remission, disease-free survival, event-free survival, and a four-month event-free survival measure. Some secondary analyses are described by calculated remission strata, while another event-free survival analysis is described by randomized strata. These labels matter because the basis for classifying participants differs across analyses.

Across the posted event-free survival results, the overall comparison points in a different direction from the primary overall-survival estimate, and the reported short-term event-free survival proportions also favor the combination group. This pattern is useful context, but it should not be treated as a substitute for the primary endpoint or as proof that the primary and secondary outcomes conflict. They measure different events and may use different analysis populations and methods. The other outcome titles indicate additional endpoints, but numerical results for all of them are not included in the registry record described for this reading.

Secondary endpoints can help show which aspects of the disease course or treatment experience may differ between groups. Their interpretation depends on definitions, follow-up, population, and statistical method. A result on one endpoint does not automatically establish a corresponding result on another, and a pattern of findings may be influenced by the number of outcomes examined.

Unless a plan controls the chance of false-positive findings across multiple tests, secondary p-values are generally less persuasive than a prespecified primary analysis. The registry record does not report a multiplicity adjustment or a complete hierarchy for secondary testing. Thus, the secondary results are best treated as supportive or exploratory context rather than as independent confirmation of the primary overall-survival result. Their uncertainty and the possibility of selective emphasis should be kept in view.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Best Response Per Independent Response Review Panel (IRRP) Assessment - Overall and by Calculated Strata (CSR 7-April-11)
• Duration of Remission (DOR) Per IRRP Assessment-Overall and by Calculated Strata (CSR 7-April-11)
• Duration of Remission (DOR) Per IRRP Assessment-Overall and by Randomized Strata (CSR 9-July-12)
• Disease-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
• Disease-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
• Event-free Survival by IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)
• Event-free Survival by IRRP Assessment - Overall and by Randomized Strata (CSR 9-July-12)
• Four-Month Event-free Survival Per IRRP Assessment - Overall and by Calculated Strata (CSR 7-April-11)

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports a Log Rank analysis for overall survival and gives a hazard ratio with a 95% confidence interval. The primary outcome is time-to-event data, meaning that the analysis concerns the time from a defined origin, randomization, to a defined event, death from any cause. Participants without a recorded event during observed follow-up can still contribute information up to the point their follow-up ends, subject to the analysis's censoring rules. Those detailed rules are not reported in the registry record.

What does a hazard ratio describe?

A hazard is the instantaneous event rate among participants who have not yet experienced the event, considered over follow-up. A hazard ratio compares that rate between groups under the model or test used. A value of 1.00 indicates equal estimated event rates; values below or above 1.00 indicate lower or higher rates in the first-listed group relative to the comparator, respectively. This is a relative, time-to-event measure, not a difference in median months and not a ratio of the total number of deaths.

The overall-survival hazard ratio is reported as 1.00. The registry also reports subgroup hazard ratios of 1.13 and 0.85 for the two calculated remission-duration strata. These estimates summarize the reported comparisons; they should not be read as direct comparisons of one stratum with another. A hazard ratio can be hard to interpret as a single summary if the relative event rates change over time. Whether that assumption is appropriate cannot be determined from the estimates alone, and further assessment is not reported in the registry record.

What does the Log Rank test contribute?

The Log Rank test compares the observed pattern of events over time between groups, taking account of the timing of events and the risk sets during follow-up. Its p-value tests a null hypothesis of no difference in the time-to-event distributions under the test's assumptions. It does not measure the size or clinical importance of an effect. The hazard ratio and its interval provide an estimate and uncertainty, while the p-value provides a test result; these answer related but different questions.

The primary p-value is 0.995. For the calculated strata, the reported p-values are 0.467 and 0.396. These values should be read alongside the hazard ratios and confidence intervals, not as stand-alone evidence. The registry record does not report whether proportional hazards were assessed, whether any alternative model was used, or whether the test was adjusted for other covariates.

Why distinguish the analysis population and strata?

The primary population is the Full Analysis Set, defined in the record as randomized participants whose baseline AML diagnosis was centrally confirmed. The registry describes the remission strata as calculated from case report forms and says they do not include IVRS mistakes. It also distinguishes calculated strata in the primary analysis title from randomized strata in some secondary outcome titles. Differences in stratum definitions or analysis populations can change who contributes to an estimate. As a result, subgroup estimates should be interpreted with their stated population and classification method in mind.

Randomization supports a comparison of assigned groups, but it does not guarantee that every analysis uses an identical set of participants or identical subgroup definitions. The registry's description of one placebo-group participant whose stratum could not be determined is incomplete. The full handling of missing or uncertain stratum information is not reported in the registry record.

How should planning illustrations be read?

Any sample-size illustrations based on observed effects are planning calculations, not observed power and not evidence that the completed study had a particular probability of detecting an effect. The record describes these illustrations as using a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the figures concern total events, using the Schoenfeld approach. For other outcomes, they concern participants per arm. These assumptions define hypothetical planning scenarios and do not establish that they were the trial's original design assumptions.

In general, over-dispersion matters when variation in data is greater than a model assumes, because standard errors and tests can then be misleading if that extra variation is ignored. That concept does not establish that over-dispersion was relevant to this time-to-event analysis. The registry does not report an over-dispersion assessment for the primary endpoint, and no such adjustment should be inferred.

Overall, the reported statistical approach is a randomized-group time-to-event comparison using a Log Rank test and hazard ratio. Further details of the statistical analysis plan, including censoring specifications, model checks, covariate adjustment, and handling of analysis deviations, are not reported in the registry record.

11. Confidence Intervals and Precision

The 95% confidence interval for the overall-survival hazard ratio is 0.78 to 1.28 around the reported estimate of 1.00. In general, a confidence interval describes a range of estimates compatible with the data under the analysis and its assumptions. It conveys uncertainty about the effect estimate; it is not a range that contains a known treatment effect with a 95% probability after the data have been observed.

Because the interval includes 1.00, it includes the value corresponding to equal estimated event rates. It also extends below and above that value, reflecting uncertainty in both directions. The interval does not establish equivalence: a formal equivalence claim would require a prespecified margin and an analysis designed to assess that question. The margin and any equivalence analysis are not reported in the registry record.

The median estimates also have uncertainty. The combination group's median was 6.6 months, with a 95% confidence interval from 5.1 to 9.3 months. The placebo-plus-cytarabine group's median was 6.4 months, with a 95% confidence interval from 4.7 to 7.3 months. These intervals overlap, but overlap alone is not a formal test of the difference between groups. The reported hazard ratio and Log Rank analysis are the registry's direct comparative statistics.

The stratum-specific hazard-ratio intervals are wider than a single point estimate can convey: 0.81 to 1.57 for remission less than 6 months and 0.58 to 1.24 for remission at least 6 months. Both include 1.00. This indicates that the subgroup estimates do not locate the relative effect precisely. Subgroup analyses generally have less information than the overall comparison, and the registry record does not report a formal test of interaction between the strata.

Precision is not the same as importance. A narrow interval can still surround an effect that is not meaningful for a particular decision, and a wide interval can leave important effects unresolved. The record's confidence intervals quantify statistical uncertainty under the reported analyses; they do not capture every source of uncertainty, such as missing details of follow-up or analysis procedures.

12. Analyses Reported by the Sponsor

The overall-survival hazard ratio, confidence interval, and p-value in the posted results are the sponsor-reported analysis: hazard ratio 1.00, 95% confidence interval 0.78 to 1.28, and p=0.995 by the Log Rank method. The subgroup comparisons are also reported by the sponsor, with hazard ratios 1.13 and 0.85 and their corresponding intervals and p-values.

The registry record does not flag a discrepancy between the posted summary and the sponsor's reported analysis. For this time-to-event outcome, interpretation therefore relies on the sponsor-reported hazard ratios rather than a new hazard-ratio calculation from medians or other summary statistics. A hazard ratio cannot be reconstructed reliably from the reported medians alone, because it depends on the event and follow-up information used in the original analysis.

Where simple recalculations are available for other outcome types, they are unadjusted calculations from posted summary information and should not replace an analysis specified and conducted by the sponsor. The general principle is that the sponsor's own analysis takes precedence when there is a discrepancy. No discrepancy is flagged for the primary result in this record.

The registry does not provide enough detail to reproduce the primary time-to-event analysis independently, including full participant-level follow-up, censoring information, and analysis specifications. The reported analysis can be described and interpreted, but it cannot be independently recreated from the medians and confidence intervals alone.

13. Multiplicity, Missing Data and Analysis Populations

The record identifies overall survival as the primary outcome and lists multiple secondary outcomes, including response and several time-to-event measures. When many outcomes or subgroup comparisons are tested, the chance of at least one small p-value can rise even if there is no underlying effect. Statistical methods can address this multiplicity by prespecifying a testing sequence, adjusting significance levels, or using other planned procedures. The registry record does not report whether such a method was used, how outcome testing was ordered, or which analyses were considered confirmatory.

Accordingly, secondary p-values should not be interpreted as though each were the sole planned test. The primary overall-survival comparison provides the clearest basis for the main statistical reading, while secondary findings add context with lower evidential weight when multiplicity control is unreported. This does not mean the secondary findings are necessarily false; it means their nominal p-values do not, by themselves, address the chance of false-positive findings across the full set of analyses.

Missing-data and censoring procedures are particularly relevant to time-to-event outcomes. Participants may have follow-up that ends without a recorded death, and the analysis must specify how such observations contribute. The registry defines overall survival but does not report detailed censoring rules, follow-up completeness, reasons for loss to follow-up, or sensitivity analyses for missing outcome data. These details should not be inferred.

The analysis population is described as the Full Analysis Set, comprising randomized participants whose baseline AML diagnosis was centrally confirmed. The record also describes calculated remission strata based on case report forms, excluding IVRS mistakes, and notes one placebo-group participant whose stratum could not be determined. The full disposition of participants and the handling of missing baseline or outcome information are not reported in the registry record.

These omissions limit assessment of robustness. The record does not report the full protocol statistical plan, interim analyses, sample-size justification, prespecified subgroup hypotheses, or the procedures used for all analysis deviations. It is therefore not possible to determine from the registry record whether every analysis was prespecified or how missingness and multiplicity were handled beyond the information explicitly stated.

14. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (15.5%), pneumonia (8.1%), pyrexia (5.8%), sepsis (5.0%), bacteraemia (4.3%).

The registry lists serious adverse event summaries for the two treatment groups. In the clofarabine-plus-cytarabine group, 97 participants are recorded as affected among 161 at risk for serious adverse events. In the placebo-plus-cytarabine group, 76 are recorded as affected among 155 at risk. The record also lists 161 and 154 participants affected by other adverse events among 161 and 155 at risk, respectively. These are group-level counts as recorded and are not an estimate of comparative risk adjusted for follow-up or other factors.

The most frequently listed serious adverse event terms include febrile neutropenia at 15.5%, pneumonia at 8.1%, pyrexia at 5.8%, sepsis at 5.0%, bacteraemia at 4.3%, and enterococcal bacteraemia at 3.7%. These terms describe reported serious events; the registry record does not give additional detail about timing, duration, recurrence, or attribution to study treatment.

Adverse-event counts require context. Participants may experience more than one event, and a participant can contribute to more than one event category, so event terms should not be added to infer a participant total. The record's listed denominators and affected counts are not interchangeable with the enrollment number. Death counts are not reported in the registry record. The information supports a descriptive reading of recorded serious-event summaries, not a complete comparative safety assessment or a treatment recommendation.

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

The primary analysis answers a specific statistical question: how overall survival from randomization compared between the randomized groups in the recorded Full Analysis Set. The reported median estimates are close, and the sponsor-reported hazard ratio is centered at 1.00 with a confidence interval that includes values below and above 1.00. The reported p-value does not indicate evidence of a difference under the Log Rank test, but it does not prove that the groups are equivalent.

The result does not show that every participant had the same outcome, nor does it predict an individual's survival. A group median is not an individual prognosis. The hazard ratio summarizes relative event rates under its assumptions and does not directly state a difference in months or explain the mechanism behind any observed pattern.

The result also does not answer every question about treatment. Event-free survival, remission, response, disease-free survival, and serious adverse events are distinct outcomes. Their results may inform context, but they do not replace the primary overall-survival estimate. The registry record does not report a formal equivalence margin, a comprehensive multiplicity procedure, detailed censoring rules, or all planned analysis details.

Subgroup estimates by remission duration are not definitive evidence that the comparison differs by stratum. Their intervals include 1.00, and the record does not report a formal interaction test. Different numerical estimates across strata can arise from sampling uncertainty, particularly when subgroup estimates are less precise.

In short, the posted primary data support a cautious statement about the measured comparison: the reported overall-survival analysis did not show a separation between the groups, while its confidence interval leaves a range of relative effects unresolved. This statistical reading is limited to the registry's recorded population, endpoint, follow-up description, and reported analysis. It neither recommends a treatment nor settles questions that the registry does not document.

16. Why This Trial Matters Statistically

This trial illustrates why the choice of endpoint and estimand matters in clinical research. Overall survival is a direct time-to-event measure with death from any cause as its event, while remission, response, and event-free outcomes capture other aspects of the disease course. Results on these different measures need not move in parallel, and each must be interpreted according to its definition and analysis population.

It also demonstrates the distinction between a point estimate and its precision. The primary hazard ratio is 1.00, but the confidence interval spans values on both sides of that estimate. The p-value alone cannot establish equivalence or show that a clinically important effect has been excluded. Statistical interpretation therefore requires the estimate, interval, test, population, and endpoint definition together.

The remission-duration analyses highlight a common challenge in subgroup interpretation. Stratification can be part of trial design, yet analyses based on calculated rather than randomized strata may differ in classification. Subgroups also contain less information than the overall trial comparison, and the record does not report an interaction test. Subgroup point estimates should not be treated as proof of effect modification.

Finally, multiple secondary outcomes can offer useful context while also raising multiplicity concerns. Without a reported testing hierarchy or adjustment, nominal secondary p-values carry less weight than the primary analysis. This is a reminder to distinguish evidence that was designated as primary from additional findings that may be supportive, exploratory, or subject to chance selection.

17. 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 registry record leaves important details unavailable for a full independent appraisal. It defines overall survival and gives the analysis timeframe, but detailed censoring rules, completeness of follow-up, and sensitivity analyses are not reported in the registry record. These are relevant to judging how robust a time-to-event estimate is when follow-up differs among participants.

The primary analysis population is described as the Full Analysis Set of randomized participants whose baseline AML diagnosis was centrally confirmed. However, full participant disposition and the treatment of all missing or unconfirmed data are not reported. The remission strata are calculated from case report forms and exclude IVRS mistakes; the record also notes that one placebo-group participant could not be assigned a stratum. Further details of that handling are not reported in the registry record.

The registry provides reported hazard ratios and confidence intervals but does not include enough information to reconstruct the primary analysis independently. The complete statistical analysis plan, model checks, covariate adjustments, handling of protocol deviations, and assessment of proportional hazards are not reported in the registry record. The record also does not report an equivalence margin or formal interaction analysis for the subgroups.

Several secondary outcomes are listed, but their existence alone does not establish a prespecified testing hierarchy. Multiplicity procedures and interim analyses are not reported in the registry record. Consequently, nominal findings among secondary outcomes require caution. The planning illustrations based on observed effects should not be mistaken for the trial's original sample-size justification or observed power; the original justification is not reported in the registry record.

The adverse-event summaries are descriptive, and the record does not report death counts in the listed safety details. Detailed timing, attribution, recurrence, and exposure-adjusted safety analyses are also not reported in the registry record. These limits constrain comparisons and should remain visible when interpreting the study's overall evidence.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia (AML)(CLASSIC I) — NCT00317642.
• Registry record last updated 2014-04-14; status last verified 2014-03.
• Results first posted 2011-09-15.
• 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.

21. Record Summary

This completed Phase III randomized, double-blind, controlled, parallel-group study compared clofarabine plus cytarabine with placebo plus cytarabine in adults 55 years and older with relapsed or refractory AML after up to two prior induction regimens. The registry records enrollment of 326 and a study period beginning 2006-08, with primary completion in 2012-01.

The primary outcome was overall survival from randomization to death from any cause, assessed in the Full Analysis Set up to approximately 4 years. The reported median estimates were 6.6 months and 6.4 months. The sponsor-reported hazard ratio was 1.00, with a 95% confidence interval from 0.78 to 1.28 and p=0.995 by the Log Rank method.

The primary estimate does not establish equivalence, and the interval leaves uncertainty about the relative effect. Secondary endpoints and serious adverse event summaries provide additional context, but multiplicity procedures and several analysis details are not reported in the registry record. The findings should be interpreted within those limits.