Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia (NCT00695903), a randomized phase 2 study. The primary outcome is Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations.

2. Clinical Question

The registry describes a Phase 2 study intended to compare the safety and efficacy of the two monotherapies and to assess pharmacokinetics. The posted primary outcome is specifically a safety count: participants with elevated creatine phosphokinase (CPK) during therapy or shortly after it. It is not a measure of bacterial clearance, cure, or comparative efficacy.

The study also lists treatment cure at the end-of-therapy visit and at the test-of-cure/safety visit as secondary outcomes. Their names are recorded, but their results are not reported in the registry record. The primary question that can be answered from the posted result is therefore narrow: how many people in the safety population met the stated CPK threshold, and how uncertain is the estimated difference between arms?

3. Trial Design

This was a Phase 2, randomized, parallel-group study of daptomycin and high-dose vancomycin for MRSA bacteremia, including right-sided infective endocarditis. The registry lists an enrollment of 38 and a terminated status. The reason for termination is not reported in the registry record. The listed study start was 2008-09-17 and primary completion was 2010-08-24.

The registry classifies allocation as randomized, the model as parallel, and masking as quadruple. The official title describes the study as double-blinded. The record does not explain the masking terminology further. The intervention arms were daptomycin 10 mg/kg IV every 24 hours and vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL.

The primary outcome concerns participants with treatment-emergent CPK elevations at least 5 x the upper limit of normal, defined as at least 1,000 U/L, by the end-of-therapy visit. Its timeframe is during therapy and up to 3 days post-therapy; treatment duration ranged from 2 to 43 days. The safety population included participants who received at least one dose. Two participants randomized to high-dose vancomycin were not treated and were excluded from that population.

The study goals also included efficacy and pharmacokinetics. Treatment cure at the end-of-therapy visit and at the test-of-cure/safety visit are listed as secondary outcomes, but their results are not reported in the registry record. Further details about the protocol, including the reason the trial was terminated, 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.

Had End of Therapy (EOT) Assessment

Reasons for not completing this period:

Had Test of Cure (TOC) Assessment

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All subjects who received at least one dose of study medication (Safety Population). Two patients in the high-dose vancomycin arm were randomized but not treated and therefore not included in the safety population.

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 Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations, measured over On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days).

The primary endpoint counts participants who had a treatment-emergent CPK elevation at least 5 x the upper limit of normal, with the threshold defined as at least 1,000 U/L, by the end-of-therapy visit. CPK is an enzyme measured in blood; an elevation meeting the stated threshold is the event being counted. The registry defines the relevant period as on therapy and up to 3 days after therapy. Treatment duration ranged from 2 to 43 days.

This is a binary outcome at the participant level: each person either met the endpoint definition or did not. Reporting the number with the event in each arm describes the observed frequency of this specified laboratory safety finding in the safety population. Comparing the arm-specific risks can then describe the magnitude and uncertainty of the difference, while retaining the endpoint’s specific definition.

The endpoint is used as a safety measure, not as an efficacy outcome. It does not by itself describe symptoms, severity beyond the laboratory threshold, causation, or the full safety profile. The registry lists treatment cure at the end-of-therapy and test-of-cure/safety visits as secondary outcomes, but those results are not reported in the registry record. The posted primary endpoint therefore supports an interpretation about this CPK threshold only, not a broader conclusion about cure or overall clinical benefit.

7. Results Posted in the Registry

• Vancomycin High-dose: 0.0% (0/17) versus 10.5% (2/19) on control; risk difference -10.5 percentage points (95% CI -24.3 to 3.3); unadjusted two-proportion z-test p = 0.169.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a participant-level event count. A participant qualifies as having the event if treatment-emergent CPK reaches at least 5 x the upper limit of normal, defined as at least 1,000 U/L, by the end-of-therapy visit. For a binary outcome, the event count is commonly interpreted alongside the number of participants assessed, because the count alone does not convey the observed risk. In this study, the safety population consists of those who received at least one dose of study medication.

What does the risk difference express?

In general, a risk difference subtracts the event risk in one group from the event risk in another. A value of zero corresponds to equal observed risks; a negative or positive value indicates the direction of the contrast, depending on which group is subtracted from which. The registry’s comparison is for high-dose vancomycin relative to daptomycin, and the reported estimate is -0.105. This direction is consistent with the observed counts: 0 participants in the vancomycin arm and 2 in the daptomycin arm met the endpoint definition.

A risk difference describes an absolute contrast, rather than a relative ratio. Its interpretation depends on the endpoint definition and the groups being compared. It does not establish why an event occurred, nor does it automatically generalize to other safety outcomes or patient groups.

How should the p-value be read?

In general, a p-value measures how compatible the observed data are with a specified null model, assuming that model and the analysis assumptions are correct. The reported unadjusted p-value is 0.169. It is not the probability that the null hypothesis is true, and it is not a measure of the size or clinical importance of a difference. The record does not report an adjusted p-value or a detailed description of the test used.

What does a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimate. It indicates which values are reasonably compatible with the data under the method’s assumptions; it does not guarantee that the true value lies within the particular interval. The comparative interval runs from -0.243 to 0.033. Because it includes zero, the result is compatible with no difference as well as with differences in either direction. The width also signals that the comparison does not estimate the contrast precisely.

The registry lists an arm-level interval of 2.9% to 31.4% for daptomycin. It gives no interval bounds for the vancomycin arm, where the event count was zero. A zero count can occur even when the underlying event risk is not zero, particularly when the available information is limited; it should not be interpreted as a guarantee of no risk.

Why does event sparsity matter?

In general, estimates based on few observed events are sensitive to each event and can have substantial uncertainty. Standard approximations can also behave poorly when counts are sparse or a group has no events. The registry record does not describe the method used to calculate the confidence intervals, so the particular interval procedure cannot be assessed from the posted information alone. The reported comparative estimate and interval should be interpreted as registry results rather than reconstructed using an assumed method.

What is the role of planning estimates?

In general, sample-size planning asks how many participants per arm might be needed under chosen assumptions about the effect to detect, significance level, allocation, and statistical method. The planning illustrations associated with the posted results are based on the observed effect and specified assumptions, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such calculations are illustrations, not the trial’s documented design rationale and not observed power. The registry record does not report the trial’s sample-size justification or enough detail to establish that these planning assumptions were used when the study was designed.

More broadly, a complete analysis description would identify the planned test, confidence-interval method, handling of missing outcome data, and any adjustments for multiple outcomes or interim analyses. Those details are not reported in the registry record. Accordingly, the interpretation should stay close to the posted counts, estimate, interval, and unadjusted p-value, without assuming unreported analytic choices.

10. Confidence Intervals and Precision

The comparative estimate is a risk difference of -0.105 for high-dose vancomycin relative to daptomycin. Its 95% confidence interval ranges from -0.243 to 0.033. This interval includes zero, so the posted data do not pin down a difference in either direction with precision. Values below zero and above zero remain compatible with the interval’s method and assumptions.

In general, a confidence interval is a way to express statistical uncertainty around an estimate, not a guarantee about the true effect. A wide interval can reflect limited information, including a small number of observed events. Here, the endpoint counts were 2 in the daptomycin arm and 0 in the high-dose vancomycin arm. Such sparse counts make a numerical contrast particularly uncertain. The registry’s arm-level interval for daptomycin is 2.9% to 31.4%; it reports no interval bounds for the zero-event vancomycin arm.

The p-value of 0.169 is unadjusted. It should be read together with the estimate and interval, not as a substitute for them. A p-value alone does not show the range of plausible differences, and a result that does not rule out zero does not establish equivalence. The registry record does not report a noninferiority or equivalence margin, so neither type of conclusion is supported by the posted comparison.

Precision concerns this CPK endpoint in the safety population. It does not describe uncertainty for efficacy outcomes, pharmacokinetics, or the broader set of adverse events. Results for the listed cure outcomes are not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary CPK safety outcome and two secondary treatment-cure outcomes: cure at the end-of-therapy visit and cure at the test-of-cure/safety visit. Their results are not reported in the registry record. The record does not describe a multiple-comparison strategy, such as a hierarchy of tests or an adjustment to account for examining multiple outcomes. It also does not report whether interim analyses were planned or conducted. Without those details, the unadjusted p-value should not be treated as evidence that accounts for all possible comparisons.

The primary outcome population is described as all subjects who received at least one dose of study medication. Two participants randomized to high-dose vancomycin were not treated and were therefore excluded from the safety population. This distinction matters: the posted primary endpoint is based on treated participants, not every randomized participant. The registry record does not report a detailed analysis of all randomized participants for this safety endpoint.

The endpoint timeframe is on therapy and up to 3 days post-therapy, with treatment duration ranging from 2 to 43 days. The record does not explain how incomplete follow-up, missing CPK measurements, or early discontinuation were handled. It also does not report how missing data were counted or whether sensitivity analyses were conducted. These details are important when interpreting an event count because participants may differ in how much time or opportunity they had for an event to be detected.

The study is listed as terminated, but the reason for termination and any resulting effect on follow-up or outcome reporting are not reported in the registry record. The analysis plan, sample-size justification, and interim-analysis details are also not reported in the registry record. These absences limit assessment of whether the posted analyses fully reflect the original plan. They do not change the reported counts, but they constrain how broadly the comparison can be interpreted.

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: diarrhoea (10.5%), endocarditis bacterial (5.9%), osteomyelitis (5.9%), renal failure (5.9%), renal failure acute (5.9%).

The primary safety outcome counts participants with treatment-emergent CPK elevations at least 5 x the upper limit of normal, defined as at least 1,000 U/L, by the end-of-therapy visit. The posted counts are 2 in the daptomycin arm and 0 in the high-dose vancomycin arm. The safety population includes participants who received at least one dose; two randomized participants in the vancomycin arm were not treated and were excluded.

The registry also reports serious and other adverse-event counts by group. Serious adverse events are listed for 3 of 19 participants at risk in the daptomycin group and 4 of 17 at risk in the vancomycin group. Other adverse events are listed for 6 of 19 and 10 of 17, respectively. These categories are distinct from the primary CPK endpoint, and the counts should not be treated as a direct comparison of overall safety without further definitions and analysis.

The registry lists serious-event terms with percentages, including Diarrhoea at 10.5%, Endocarditis bacterial at 5.9%, Osteomyelitis at 5.9%, Renal failure at 5.9%, Renal failure acute at 5.9%, and Atrioventricular block complete at 5.3%. The record does not provide context sufficient to attribute these events to a treatment or to infer their comparative frequency from these entries alone. A listed event does not by itself establish causation.

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

The posted primary result describes a specific laboratory safety outcome in the treated safety population: 2 participants in the daptomycin arm and 0 in the high-dose vancomycin arm had treatment-emergent CPK elevations meeting the stated threshold. The estimated risk difference for vancomycin relative to daptomycin is -0.105, with a 95% confidence interval from -0.243 to 0.033 and an unadjusted p-value of 0.169.

These results do not provide a precise estimate of the difference. The interval includes zero and is compatible with effects in either direction. The absence of observed events in one arm does not show that the underlying risk is zero. Nor does the result establish that the treatments are equivalent, noninferior, or different in overall safety. The registry record does not report an equivalence or noninferiority margin.

The result also does not answer whether either regimen improves cure or other clinical outcomes. Cure at the end-of-therapy and test-of-cure/safety visits are listed as secondary outcomes, but their results are not reported in the registry record. Although the study goals included pharmacokinetics, relevant results are not reported in the registry record. The primary finding cannot stand in for those outcomes.

Interpretation is further bounded by the safety population definition, the exclusion of two randomized but untreated vancomycin participants, sparse primary events, and limited reporting about missing data and analysis methods. The study is listed as terminated, but the reason and consequences for follow-up are not reported in the registry record. These limits call for a narrow reading: the posted data describe the observed CPK events and an uncertain between-arm contrast, rather than a definitive clinical comparison.

14. Why This Trial Matters Statistically

This study illustrates why a count, an effect estimate, and its uncertainty answer different questions. The event counts show what was observed in the safety population: 2 participants in the daptomycin arm and 0 in the high-dose vancomycin arm met the CPK endpoint. The risk difference expresses the direction and magnitude of the estimated contrast, while its confidence interval communicates how uncertain that estimate is. Here, the interval from -0.243 to 0.033 includes zero, so the count difference alone should not be mistaken for a conclusive treatment difference.

The example also shows how the analysis population affects a safety result. The primary outcome includes participants who received at least one dose, while two randomized vancomycin participants were not treated and were excluded. The randomized and treated populations are not interchangeable, and a reader needs the population definition to understand which people contribute to an outcome.

Finally, the registry separates a stated study goal from results available for interpretation. The trial aimed to compare safety and efficacy and assess pharmacokinetics, but the posted primary result is a CPK safety count; the listed cure outcomes have no results reported in the registry record. The record’s terminated status, without a reported reason, and the absence of detailed analytic and missing-data methods further limit inference. Together, these features make the study a useful example of the need to match conclusions to the endpoint and information actually reported.

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 primary comparison rests on few observed CPK events: 2 participants in the daptomycin arm and 0 in the high-dose vancomycin arm. The resulting risk-difference interval, -0.243 to 0.033, includes zero and allows substantial uncertainty about the direction and size of the contrast. A zero count in one arm should not be interpreted as proof of zero underlying risk.

The safety population included participants who received at least one dose, and two randomized participants in the vancomycin arm were not treated and were excluded. The registry record does not report a corresponding randomized-population analysis for this endpoint. Nor does it explain how missing CPK measurements, incomplete follow-up, or early discontinuation were handled. The endpoint timeframe spans therapy and up to 3 days post-therapy, while treatment duration ranged from 2 to 43 days.

The trial is listed as terminated, but the reason for termination and its effect on follow-up or reporting are not reported in the registry record. The record also does not report the sample-size justification, detailed statistical analysis plan, confidence-interval method, interim-analysis plan, or multiplicity approach. This makes it difficult to assess the planned relationship between the primary and secondary analyses.

Although treatment cure and pharmacokinetics were among the study goals, cure outcomes are listed without results, and pharmacokinetic results are not reported in the registry record. The primary finding therefore cannot support conclusions about efficacy or overall safety. The serious and other adverse-event counts provide additional descriptive information, but the record does not establish causal attribution or a comprehensive comparative safety analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia — NCT00695903.
• Registry record last updated 2018-12-24; status last verified 2018-12.
• Results first posted 2011-12-06.
• 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

NCT00695903 is a Phase 2 randomized, parallel-group study of daptomycin 10 mg/kg IV every 24 hours and high-dose vancomycin for MRSA bacteremia, including right-sided infective endocarditis. The registry lists an enrollment of 38, quadruple masking, and a terminated status; the reason for termination is not reported in the registry record.

The primary outcome counts treatment-emergent CPK elevations at least 5 x the upper limit of normal, defined as at least 1,000 U/L, among participants who received at least one dose. The posted counts are 2 in the daptomycin arm and 0 in the vancomycin arm. The risk difference for vancomycin relative to daptomycin is -0.105, with a 95% confidence interval from -0.243 to 0.033 and an unadjusted p-value of 0.169. The interval includes zero and indicates substantial uncertainty. Results for the listed treatment-cure outcomes are not reported in the registry record.