Daptomycin Versus Placebo in Patients With Neutropenia and Fever: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Daptomycin Versus Placebo in Patients With Neutropenia and Fever (NCT01216241), a randomized phase 3 study. The primary outcome is Percentage of Afebrile Neutropenic Subjects.

2. Clinical Question

3. Trial Design

This is a Phase 3, randomized, parallel-group study described in its official title as single-center, double-blind, and comparative. The registry record classifies masking as triple. Random allocation is intended to reduce systematic differences in treatment assignment, while masking is intended to limit influences from knowing which treatment was assigned. The record does not specify which people were masked or how masking was maintained, so those details cannot be assessed from the registry information.

The listed enrollment is 36. This is the registry enrollment figure and should not be treated as the denominator for every outcome: the primary outcome entries list group denominators of 4 and 6, while the safety entries list 18 at risk in each group. The record does not explain the difference among those recorded populations or establish how many participants contributed to each analysis beyond the outcome-specific figures.

The treatment groups are daptomycin and saline placebo. Daptomycin is described as intravenous 8mg/kg once per day for 5-10 days; saline solution is the placebo description. The registry record lists the study status as terminated. Its recorded start is 2011-04, and primary completion is recorded as 2013-04. The reason for termination and the circumstances surrounding the study's completion are not reported in the registry record.

The sponsor is the University of Rochester. Although the record identifies randomization, masking, a parallel model, phase, enrollment, and status, it does not report the randomization procedure, allocation concealment, detailed protocol, or a statistical analysis plan. Those omissions limit the ability to judge implementation and planned analyses from the registry record alone.

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: All subjects, once consent was obtained were considered enrolled. If they developed a fever they were then randomized to study drug or placebo. If they did not develop neutropenic fever they did not receive study drug or placebo.

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 Percentage of Afebrile Neutropenic Subjects, measured over 5 days.

The primary endpoint is titled “Percentage of Afebrile Neutropenic Subjects.” It asks whether neutropenic subjects become afebrile by five days after fever first develops. The registry describes the measure as a number of participants and identifies the outcome as binary, meaning that the recorded outcome concerns whether an event occurred for each participant. Becoming afebrile by the stated time is the event of interest.

A fixed-time clinical outcome can provide an interpretable summary of whether participants reached a defined state within a specified period. Comparing the proportion who reach that state across randomized groups can be useful because it relates the result to a clearly described event and time frame. The endpoint's title uses “percentage,” but the posted arm entries are counts, with a value of 1 recorded for each group and denominators of 4 for daptomycin and 6 for saline placebo. The registry record does not give a usable comparative estimate or explain the difference between these outcome denominators and the enrollment or safety figures.

The five-day time frame is anchored to the onset of fever according to the endpoint description. Further operational definitions, such as the temperature criterion for being afebrile, the measurement schedule, and rules for handling missing measurements, are not reported in the registry record. Without those details, the endpoint's clinical interpretation and reproducibility cannot be fully evaluated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a binary primary outcome and says that a two-arm comparison is not estimable. It reports no analyses. The statistical concepts below are general explanations of how such outcomes are commonly considered; they are not claims about methods used in this trial unless the registry record explicitly says so.

What does a binary outcome represent?

General: A binary outcome classifies each participant according to whether a defined event occurred. For this trial, the specified event is becoming afebrile by five days after fever first develops. A group summary may report the number of participants with the event, the number assessed, or a proportion. A comparison then describes how the event occurrence differs between treatment groups. The registry entries provide event counts and outcome denominators, but they do not provide an estimable comparison.

For a useful group comparison, the event definition, assessment period, analysis population, and handling of participants without an observed outcome need to be clear. If these details are absent, readers cannot determine whether group summaries refer to comparable populations or how incomplete observations were treated. The registry record does not report those analysis details for the primary outcome.

Why is an effect estimate useful?

General: An effect estimate expresses the observed contrast between groups on a stated scale. For a binary outcome, possible scales include a difference in proportions or a ratio of proportions. Each scale answers the comparison in a different way. The registry record does not report an estimate on any such scale, and none can be substituted for the sponsor's missing comparison by treating the posted entries as a complete analysis.

A confidence interval is a range of values produced by a statistical method that conveys uncertainty around an estimate. In general, a narrower interval indicates greater precision under the assumptions of that method, while a wider interval indicates more uncertainty. The interval does not guarantee that the true effect lies within its limits, and it does not by itself establish clinical importance. No confidence interval for the primary treatment comparison is reported in the registry record.

A p-value, when reported, is a measure of how incompatible the observed data are with a specified null model under the chosen statistical assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. No p-value is reported for this comparison. Therefore, statistical significance cannot be assessed from the posted primary outcome entries.

What can be learned from the recorded counts?

The arm records list one event in each group, with outcome denominators of 4 for daptomycin and 6 for saline placebo. These are descriptive registry entries, not a reported inferential analysis. The record's note that a binary two-arm comparison is missing or not estimable means that a treatment contrast and its uncertainty should not be reconstructed from these entries. In particular, the record does not explain whether the listed denominators reflect the full intended outcome populations, a subset with available measurements, or another analysis set.

General: Small amounts of outcome information can yield unstable estimates, especially when the event is uncommon or data are incomplete. Statistical methods may behave differently depending on the number of observed events and the analysis assumptions. This general point does not establish why a comparison is unavailable in this trial; the registry does not state the reason.

How should the planning illustration be understood?

The sample-size assumptions describe a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation. The illustration considers a stated fraction of the observed effect as the effect to detect. It is not the trial's own design justification, and the registry record does not report that these were the assumptions used to design or conduct the trial.

General: A sample-size calculation estimates how much information a future study might need under specified assumptions about the effect, variability, allocation, and analysis. Such a calculation is conditional on those assumptions. A planning illustration based on an observed effect is not a measure of the probability that the completed study detected an effect, and it should not be described as observed power. Because the primary comparison is not estimable in the registry record, the planning illustration should not be read as repairing or replacing the missing trial analysis.

The record does not report the statistical model, any adjustment variables, a pre-specified analysis method, or a plan for handling missing outcome data. It also reports no interim analyses. Absence of these details means that readers cannot assess whether the posted entries follow a prespecified analytical approach or compare a reported sponsor analysis with a recalculation. The registry record does not provide a sponsor estimate that could take precedence over a recalculation.

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("Daptomycin", "Saline Placebo")
n      <- c(4, 6)
events <- c(1, 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  Daptomycin  4  1  25.0  0.6  80.6  4.6  69.9  5.3  71.6
ARM  Saline Placebo  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and no posted secondary outcomes. This limits what can be assessed about multiplicity, which is the issue of interpreting results when several outcomes or statistical tests are considered. The record does not report a broader testing hierarchy, multiplicity adjustment, or statistical analysis plan. It is therefore not possible to determine whether other planned outcomes or comparisons existed, or how they would have been handled.

Missing data are also important to interpretation. The primary outcome entries list denominators of 4 for daptomycin and 6 for saline placebo, while the registry enrollment is 36 and the safety record lists 18 at risk in each group. These figures should not be combined or treated as interchangeable. The registry does not describe the analysis populations, participant flow, reasons for absent outcome observations, or the handling of missing measurements. It is not possible to tell whether outcome data were unavailable, excluded, or not entered in the registry.

The registry explicitly states that a two-arm comparison for the binary endpoint is missing or not estimable, and it lists zero analyses. This is distinct from having a reported null result: no quantitative comparison is available to interpret. The record does not say whether the absence of an estimable result reflects missing observations, a reporting issue, an analytical difficulty, or another cause.

No information is reported about intention-to-treat, per-protocol, or other analysis populations. The effects of exclusions or incomplete follow-up therefore cannot be evaluated. These gaps matter because outcome definitions, analysis populations, missing-data methods, and multiplicity decisions can influence the meaning of a reported estimate. Here, the absence of a comparative estimate is the central limitation.

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: acute kidney injury (5.6%), toxic epidermal necrolysis (5.6%), acute respiratory failure (5.6%), hyperbilirubinemia (5.6%), elevated liver function tests (5.6%).

The safety record lists 18 participants at risk in each group. It records serious adverse events affecting 3 participants in the daptomycin group and 2 in the saline placebo group. Other adverse events are listed for 8 participants in the daptomycin group and 5 in the saline placebo group. These are the registry's reported counts; the record does not provide a comparative safety analysis, confidence intervals, or p-values.

The serious-event terms listed in the record are acute kidney injury, toxic epidermal necrolysis, acute respiratory failure, hyperbilirubinemia, and elevated liver function tests. Each term is accompanied by 5.6%. The registry does not clarify in this record how the percentages relate to the group denominators or provide an arm assignment for each listed term. They should therefore be read as listed event-term percentages, not as a basis for reconstructing group-specific risks.

Deaths are not reported in the registry record. The safety counts do not establish whether an adverse event was caused by study treatment, and the record does not provide details on event timing, severity beyond the serious classification, duration, or management. Differences in the recorded counts are descriptive and should not be interpreted as evidence of a treatment-related difference without an appropriate analysis and fuller context.

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

The registry record establishes that a randomized, triple-masked, parallel-group trial compared daptomycin with saline placebo for patients with neutropenia and fever. Its primary question concerns becoming afebrile by five days after fever first develops. The record also reports limited outcome counts and safety-event counts. These details describe what the registry contains, but they do not provide a completed statistical answer to the primary comparison.

In particular, the primary outcome entries list one event in each group, with denominators of 4 and 6, and the record states that a two-arm comparison is not estimable. There is no reported effect estimate or confidence interval. Without those, the direction, magnitude, and precision of a group difference cannot be established. The entries should not be interpreted as demonstrating that the treatments are equivalent, that either treatment is superior, or that no difference exists.

The safety record documents serious and other adverse-event counts, but it does not report an inferential comparison or establish causation. The listed serious-event terms and percentages are not accompanied by arm-specific term counts in the registry record. They provide a descriptive safety record, not a complete assessment of comparative risk.

The record's terminated status and the difference between the enrollment figure, outcome denominators, and safety at-risk figures add uncertainty about the available data. The reason for termination, participant flow, and explanations for these different populations are not reported. These omissions do not establish that a particular problem occurred; they limit what can be inferred.

General: Statistical evidence is most informative when the outcome definition, analysis population, effect estimate, and uncertainty are reported together. A registry record that lacks a comparative estimate cannot answer the primary question quantitatively. The strongest justified conclusion is that the registry documents the trial's intended comparison and some outcome and safety entries, while the comparative primary result remains unavailable or not estimable in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a registered research question and a reportable comparative result. The record describes randomization, masking, parallel groups, a primary endpoint, and an enrollment figure. Yet it provides no analyses and states that a two-arm comparison of the binary primary endpoint is not estimable. The design features alone cannot supply the missing treatment-effect estimate.

The record also illustrates why denominators need to be tied to a clearly specified analysis population. Enrollment is listed as 36, the primary outcome entries use denominators of 4 and 6, and the safety entries list 18 at risk in each group. Without participant flow and definitions for these populations, those quantities cannot be reconciled. Reporting the denominator behind each outcome is essential for understanding what the event counts represent.

Another statistical lesson concerns precision. A count without a comparative estimate and uncertainty measure gives little basis for evaluating the range of effects compatible with the data. In general, uncertainty is especially important when the amount of outcome information is limited. That principle explains why a descriptive count should not be mistaken for a conclusive comparison, but it does not explain why this registry record lacks an estimable result.

The sample-size assumptions are identified as a planning illustration rather than the trial's own design justification. This distinction matters: calculations based on an observed effect can be useful for planning future studies, but they do not show that the completed trial had adequate information or that it detected an effect. The record gives no sample-size rationale or statistical plan.

Finally, the terminated status and incomplete analytical reporting show how registry entries can be insufficient for drawing a comparative conclusion even when study design and some results are recorded. Clear reporting of outcome populations, missing data, analysis methods, and uncertainty is necessary for readers to understand what the results can support.

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 main trial-specific limitation is that the registry record does not provide an estimable comparison for the primary binary endpoint. It reports one event in each group, with denominators of 4 and 6, but says values are missing or not estimable for a two-arm comparison. No effect estimate, confidence interval, or p-value is available. The primary question therefore cannot be answered quantitatively from the record.

The primary outcome denominators differ from the registry enrollment figure of 36 and from the safety at-risk figures of 18 in each group. The registry does not provide participant flow or explain the populations behind these entries. It also does not report reasons for missing outcome information, rules for handling incomplete measurements, or whether the outcome entries reflect all randomized participants.

Outcome measurement details are limited. The registry specifies becoming afebrile by five days after fever first develops, but does not report the operational temperature threshold, assessment schedule, or adjudication procedures. The reason the study was terminated is not reported. These omissions limit assessment of endpoint reproducibility and the context of the incomplete result.

The record lists no analyses and no secondary posted outcomes. A statistical analysis plan, randomization details, allocation concealment methods, analysis populations, and any interim analyses are not reported in the registry record. Safety reporting is also limited: deaths are not reported, the listed serious adverse-event terms do not have clear arm-specific counts, and no comparative safety analysis is provided.

These limitations concern what the registry documents; they do not establish that procedures were absent from the study itself. They mean that readers cannot evaluate those procedures from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Daptomycin Versus Placebo in Patients With Neutropenia and Fever — NCT01216241.
• Registry record last updated 2014-04-10; status last verified 2014-03.
• Results first posted 2014-04-10.
• 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 record describes a Phase 3, randomized, triple-masked, parallel-group, single-center study sponsored by the University of Rochester. It compares intravenous daptomycin, described as 8mg/kg once per day for 5-10 days, with saline placebo in patients with neutropenia and fever. Enrollment is listed as 36, and the study status is terminated. The recorded start is 2011-04 and primary completion is 2013-04.

The primary endpoint concerns becoming afebrile by five days after fever first develops. The posted group entries record one event for daptomycin and one for saline placebo, with denominators of 4 and 6. The registry states that a two-arm comparison is missing or not estimable and lists no analyses or secondary outcomes. Safety entries list serious adverse events affecting 3 and 2 participants, respectively, and other adverse events affecting 8 and 5, with 18 at risk in each group. The reason for termination and the explanation for the different outcome and safety populations are not reported in the registry record.