Daptomycin as an Adjuvant Agent in the Treatment of Enterococcal Native Valve Endocarditis.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Daptomycin as an Adjuvant Agent in the Treatment of Enterococcal Native Valve Endocarditis. (NCT00401960), a non-randomized phase 4 study. The primary outcome is Number of Participants With Any Grade 3 or 4 Toxicity (DAIDS Scale).

2. Clinical Question

The study asked whether daptomycin, used as an adjunct to standard care, could be assessed for safety and efficacy in people with proven native valve enterococcal endocarditis. Its planned comparison was between patients who elected to receive daptomycin in addition to their existing antibiotics and patients who elected to receive standard care prescribed by their physician. Because treatment was not randomly assigned, the groups may differ in ways that affect outcomes; the comparison is not a like-for-like control comparison.

The stated safety focus included Grade 3 or 4 toxicity on the DAIDS scale and muscle or renal toxicity defined by criteria described as predefined. The stated efficacy outcomes included time to clearance of bacteremia, cure and mortality at 6 weeks following completion of antibiotic therapy, and microbiologic measures based on serum bactericidal titers and the minimum bactericidal concentration of Enterococci to daptomycin. The primary outcome listed in the registry record is the number of participants with any Grade 3 or 4 toxicity.

The record states that the study was terminated because enrollment was insufficient and that the data were not sufficient for the planned analysis. It therefore does not provide a planned comparative estimate that can answer whether the adjunctive approach changed safety or efficacy outcomes.

3. Trial Design

NCT00401960 is registered as a Phase 4, parallel, non-randomized, open-label study sponsored by Weill Medical College of Cornell University. The record describes two treatment approaches: adjunctive daptomycin with standard therapy, and standard of care alone. Patients elected which approach to receive; the record does not describe random assignment or masking. Consequently, measured differences between groups could reflect differences in the patients or care choices as well as any treatment effect.

The study began in 2006-09, had a primary completion date of 2008-10, and is listed as terminated. The enrollment recorded is 6. The study description says the investigators expected to enroll 40 patients over 2 years, but the registry record states that the study was terminated due to insufficient enrollment and that the data were not sufficient for the planned analysis. That expectation is a stated recruitment target, not the number enrolled.

The intervention was daptomycin at 8 milligrams/kilogram/day as an addition to antibiotics already being received. Participants in the standard-care group received therapy prescribed by their primary physician. The brief description frames the study as an assessment of both safety and efficacy, with clinical outcomes, microbiologic outcomes, and toxicity outcomes named. The registry record lists two outcome measures and reports no posted analyses. The record does not report a detailed statistical analysis plan, the allocation process beyond patient election, or methods used to control for differences between the groups.

Because allocation was non-randomized and masking was absent, interpretation of any between-group contrast would require particular caution. Choice of treatment can be associated with clinical status, preferences, or other factors, and open-label care can influence decisions about assessment or management. The registry record does not describe adjustment methods that would address these concerns. Most importantly, it explicitly states that enrollment was insufficient for the planned analysis, so the posted information should not be treated as a completed comparative evaluation.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Study terminated due to insufficient enrollment; therefore data not sufficient for planned analysis

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: see study inclusion criteria

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Any Grade 3 or 4 Toxicity (DAIDS Scale), measured over weekly.

The primary endpoint is the number of participants with any Grade 3 or 4 toxicity on the DAIDS scale. It is a participant-count outcome: the measure concerns whether a participant experienced a qualifying toxicity, rather than the total number of toxicity episodes. The registry lists the timeframe as weekly and refers readers to the adverse event table for details. The record does not provide further information on how repeated weekly observations were combined into the reported primary measure.

A toxicity endpoint is used to describe harms observed during treatment. A threshold based on toxicity grade focuses attention on events meeting the specified severity level, while participant counts can communicate how many people experienced such events. This is a general explanation of the endpoint type, not evidence that the study established a safety difference.

The registry record says the study was terminated due to insufficient enrollment and that data were not sufficient for the planned analysis. It does not report a completed planned analysis of this primary endpoint or a comparative estimate with uncertainty. Serious adverse event counts are also reported, but serious adverse events are not interchangeable with the primary endpoint: the endpoint specifically concerns any Grade 3 or 4 toxicity on the DAIDS scale, while the serious-event listing is a separate safety summary. The record does not provide enough detail to determine how those categories overlap.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a non-randomized, open-label, parallel study. In general, parallel designs compare outcomes across groups followed under different treatment approaches. Random assignment is often used to make groups comparable on average at the start of a study; it was not used in this study. Here, patients elected whether to receive adjunctive daptomycin or standard care. That choice can be associated with prognosis or other factors, so a group contrast cannot automatically be attributed to the treatment. The record does not report an adjustment strategy intended to account for such differences.

What does the primary outcome count?

The primary outcome is a count of participants with any Grade 3 or 4 toxicity on the DAIDS scale. In general, a binary participant outcome records whether each person met a defined event criterion. A count of participants can then describe how many met that criterion, but a count alone does not show how precisely the underlying event frequency is known. Precision depends on the amount of information available and is conveyed by uncertainty estimates such as confidence intervals. No confidence interval for the primary outcome is reported in the registry record.

The endpoint timeframe is listed as weekly. Repeated weekly assessments can raise analytic questions, including whether the endpoint counts a participant once if the criterion is met at any assessment or counts events in another way. The registry record does not report the method used to handle repeated observations for the primary analysis. It also does not give the full predefined criteria for muscle or renal toxicity in this discussion available for this record.

How should uncertainty be understood?

As a general statistical concept, an estimate describes the observed data, while a confidence interval describes the range of values reasonably compatible with those data under the analysis assumptions. Wider intervals indicate less precision. With sparse observations, estimates of event frequency can be unstable, and a lack of a reported difference is not evidence that two treatments are equivalent. Equivalence or noninferiority requires a prespecified question and analysis; those details are not reported in the registry record.

The posted safety counts should be read descriptively. They are not accompanied by an inferential comparison or a reported uncertainty interval in the registry record. Moreover, because treatment was not randomized, even a precise unadjusted contrast would not by itself resolve confounding. General methods for non-randomized comparisons may use measured covariates, but the adequacy of such adjustment depends on what was measured and how the analysis was conducted. The registry record does not report an adjusted analysis.

What do the planning assumptions mean?

The planning illustration is described as a recalculation from an observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. These assumptions are for planning illustrations, not a description of the trial's own design or analysis. The registry record does not report a formal sample-size justification for the trial, and the illustration must not be interpreted as observed power. A planning calculation asks what sample size might be needed under chosen assumptions; it does not measure the probability that the completed study detected an effect.

In general, a normal approximation simplifies calculation by using an approximate distribution for a statistic. Its suitability depends on the outcome and the amount and pattern of data. For sparse binary outcomes, approximation-based calculations can be sensitive to assumptions. The record does not provide enough detail to assess the specific recalculation beyond its stated assumptions, and no sample-size illustration can repair the study's non-randomized allocation or insufficient enrollment.

The planning notes distinguish time-to-event calculations, which give a total number of events using the Schoenfeld approach, from other calculations, which give participants per arm. This is a general distinction in planning: time-to-event power is often tied to event count, while other designs are framed in terms of group size. The study description names time to clearance of bacteremia, but the registry record does not report a completed time-to-event analysis or event-based estimate for that outcome.

What analysis details are unavailable?

The registry record reports no posted analyses. It does not report the planned statistical model, a method for handling missing observations, a multiplicity procedure, interim analyses, or an analysis population definition. These details matter because they determine which observations contribute to each estimate, how repeated outcomes are handled, and how multiple questions are interpreted. They should not be inferred from the outcome list or from the study's stated aims. The record's explicit statement that data were insufficient for the planned analysis is the clearest guide to the status of the intended statistical evaluation.

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("Adjunctive Daptomycin Group", "Standard of Care Group")
n      <- c(5, 1)
events <- c(4, 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  Adjunctive Daptomycin Group  5  4  80.0  28.4  99.5  37.6  96.4  35.9  95.7
ARM  Standard of Care Group  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2

11. Multiplicity, Missing Data and Analysis Populations

The study description names several safety, clinical efficacy, and microbiologic outcomes, including toxicity, bacteremia clearance, cure, mortality, serum bactericidal titers, and minimum bactericidal concentration. Considering multiple outcomes can increase the chance that at least one finding appears notable by chance if each is tested separately. In general, multiplicity methods can define a primary question, control the error rate across tests, or distinguish confirmatory from exploratory outcomes. The registry record does not report a multiplicity plan or explain how the various stated outcomes were to be prioritized beyond listing the primary endpoint.

Missing-data procedures and analysis populations are not reported in the registry record. The available record does not describe how incomplete follow-up, missing weekly assessments, or unavailable laboratory measures would have been handled. It also does not state whether the planned analysis was to include all enrolled participants, participants who received assigned or elected treatment, or another population. These omissions limit assessment of possible bias and of how each outcome would have been calculated.

The record reports 0 posted analyses and says the data were not sufficient for the planned analysis because of insufficient enrollment. It does not report an interim-analysis plan or a detailed statistical analysis plan. Those elements should not be assumed to have been absent from the investigators' work; they are simply not reported in the registry record. Without the planned analysis details and completed estimates, the outcomes cannot support formal conclusions about treatment differences or multiplicity-adjusted evidence.

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 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: hemopericardium (40.0%), death (20.0%), cr elevation (20.0%).

The serious adverse event summary lists 5 participants at risk and 5 affected in the adjunctive daptomycin group, and 1 at risk and 0 affected in the standard-of-care group. For other adverse events, it lists 5 at risk and 0 affected in the adjunctive group, and 1 at risk and 0 affected in the standard-of-care group. The serious-event terms listed with percentages are hemopericardium at 40.0%, death at 20.0%, and Cr elevation at 20.0%.

These are descriptive registry entries. They should not be treated as a randomized or adjusted comparison, because treatment was non-randomized and patients elected their treatment approach. The group sizes are limited, and the record states that enrollment was insufficient for the planned analysis. The listed serious-term percentages are not accompanied by a denominator or a group-specific breakdown in this summary, so they cannot be translated into group-specific event counts from the registry entry alone.

Serious adverse events and the primary endpoint are different summaries. The primary endpoint concerns participants with any Grade 3 or 4 toxicity on the DAIDS scale; the serious-event summary uses the serious-event category. The record does not explain how these categories overlap. The serious-event counts therefore should not be used as a substitute for a completed analysis of the primary toxicity endpoint, nor do they establish a comparative safety conclusion.

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

The registry record establishes that NCT00401960 was designed to examine daptomycin as an adjunct to standard therapy for enterococcal native valve endocarditis, with safety and efficacy outcomes in view. It also records the study as terminated because enrollment was insufficient and states that the data were not sufficient for the planned analysis. That information is central to interpreting the posted results: the intended comparative question was not answered by a completed planned analysis in the registry record.

The posted serious adverse event counts describe observations in the two treatment groups, and the record lists several serious-event terms with percentages. Those descriptions can identify what the registry reports, but they do not establish that the treatment caused or prevented an event. The non-randomized allocation, patient election of treatment, limited enrollment, and absence of a reported inferential analysis all constrain comparisons. The counts are not a basis for concluding that one approach is safer.

The same restraint applies to efficacy. The study description names clinical outcomes and microbiologic measurements, but the registry record does not report comparative estimates for those outcomes. The proposed hypothesis of safety and efficacy should not be mistaken for a result. The record does not show that daptomycin improved, worsened, or left unchanged any of the stated outcomes compared with standard care.

In general, absence of a statistically reported difference is not proof of equivalence, and a descriptive difference is not proof of a causal treatment effect. This distinction is especially important when groups are selected rather than randomized and when the planned analysis could not be conducted with sufficient data. Any planning calculation based on an observed effect remains a planning illustration, not observed power and not a substitute for a completed analysis.

The appropriate statistical reading is therefore narrow: the registry records the study's design, termination, insufficient enrollment for planned analysis, and descriptive safety entries. It does not establish a reliable comparative estimate of safety or efficacy. The results should be understood as incomplete evidence from a terminated, non-randomized study rather than a definitive test of the stated hypothesis.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates how design and recruitment status shape what can be learned from observed data. The study was non-randomized and open-label, and patients elected their treatment approach. Even if outcome counts are available, differences between groups can reflect selection into treatment as well as the intervention. Statistical adjustment can sometimes address measured differences, but the registry record does not report an adjusted analysis or enough detail to assess such an approach.

The recruitment history also matters. The study description expected enrollment of 40 patients over 2 years, while the registry records enrollment of 6 and states that the study was terminated due to insufficient enrollment. The record explicitly says that data were not sufficient for the planned analysis. This is not simply a question of whether a result crossed a significance threshold; the planned comparative evaluation could not be supported by the available data as described in the registry.

The record also demonstrates why a planning calculation should be separated from a trial result. Calculations based on observed effects and stated assumptions can illustrate future planning needs, but they do not supply evidence that the completed study had adequate power. They also cannot overcome non-randomized allocation, missing analysis details, or limited outcome information.

Finally, a safety listing can be useful as a descriptive account without answering a comparative causal question. Reading counts in context—design, group size, endpoint definition, analysis status, and uncertainty—is essential. In this record, those features call for caution and prevent a strong conclusion about comparative treatment effects.

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.

Several limitations are specific to this study. It was terminated, and the registry record attributes termination to insufficient enrollment. The record states that the data were not sufficient for the planned analysis. The recorded enrollment is 6, below the expectation of 40 patients over 2 years stated in the study description. The registry does not report why recruitment fell short or whether the planned analysis was revised.

Allocation was non-randomized, with patients electing whether to receive adjunctive daptomycin or standard care. The groups therefore cannot be assumed comparable at baseline. Masking was absent, so treatment knowledge could also affect care or outcome assessment. The registry record does not report a method to adjust for differences between groups, and it does not provide baseline characteristics with which to assess comparability.

The primary endpoint is defined as the number of participants with any Grade 3 or 4 toxicity on the DAIDS scale, assessed weekly, but the registry record does not describe how repeated assessments were handled in the planned analysis. It refers to an adverse event table for details, yet the posted record also states that the planned analysis was not possible with the available data. Serious adverse event summaries are reported separately, and the record does not explain their overlap with the primary endpoint.

Clinical and microbiologic efficacy outcomes are named in the study description, but comparative estimates for them are not reported in the registry record. The statistical analysis plan, missing-data methods, analysis populations, multiplicity handling, and interim-analysis procedures are also not reported. These gaps, together with limited enrollment and non-randomized treatment choice, restrict both the precision and causal interpretation of the posted information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Daptomycin as an Adjuvant Agent in the Treatment of Enterococcal Native Valve Endocarditis. — NCT00401960.
• Registry record last updated 2017-05-03; status last verified 2017-04.
• Results first posted 2017-05-03.
• 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

NCT00401960 was a Phase 4, parallel, open-label, non-randomized study sponsored by Weill Medical College of Cornell University. It examined daptomycin at 8 milligrams/kilogram/day added to standard therapy for enterococcal native valve endocarditis, compared with standard care alone. Patients elected their treatment approach.

The primary endpoint was the number of participants with any Grade 3 or 4 toxicity on the DAIDS scale, with a weekly timeframe. The study began in 2006-09, had primary completion in 2008-10, and is listed as terminated. Enrollment was 6; the study description had stated an expectation to enroll 40 patients over 2 years.

The registry record says termination was due to insufficient enrollment and the data were not sufficient for the planned analysis. It reports descriptive serious adverse event entries but no posted analyses. The record does not establish comparative safety or efficacy.