Phase 4 Efficacy and Safety Study of Cubicin® With and Without Combination Therapy in S. Aureus Infective Endocarditis (SAIE): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 4 Efficacy and Safety Study of Cubicin® With and Without Combination Therapy in S. Aureus Infective Endocarditis (SAIE) (NCT00638157), a randomized phase 4 study. The primary outcome is Summary of Clinically Significant Increases in Serum Creatinine by Visit.

2. Clinical Question

3. Trial Design

This was a Phase 4, multicenter, randomized, double-blind, parallel-group study. It compared daptomycin alone with daptomycin plus initial gentamicin in the treatment of S. aureus infective endocarditis. The arm descriptions specify right-sided infective endocarditis. The registry record lists enrollment of 24 and gives the trial status as terminated. It records a start date of 2009-02-13 and a primary completion date of 2011-11-09.

The daptomycin-alone arm used daptomycin 6 mg/kg q24h. The combination arm used the same daptomycin regimen with concomitant initial gentamicin dosed for the first 2 days of therapy. The registry record reports an overall median treatment duration of 13.0 days in both groups. It does not explain why the trial was terminated, so termination should not be attributed to a particular safety, efficacy, recruitment, or operational reason.

Random allocation is intended to reduce systematic differences between groups at the point of assignment. Double masking is intended to limit the influence of treatment knowledge on care or outcome assessment. The registry record does not describe the allocation procedure, concealment method, masking details, or whether masking was maintained throughout the study. It also does not report a planned sample-size justification or the statistical plan.

The primary outcome is a count of participants meeting a clinically significant serum-creatinine increase definition, assessed at baseline, EOT, and TOC. The listed secondary outcome is the investigator’s assessment of clinical response at TOC. Although the registry record lists two outcome measures, it reports no analyses for them. The available record therefore identifies the trial’s design and intended outcome measures but does not supply a treatment-effect estimate for the primary outcome.

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: Safety Population includes all patients who received any dose of study medication.

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: Intent-to-Treat (ITT) Population used. Includes all randomized subjects.

6. Primary Endpoint

The registry lists the primary outcome as Summary of Clinically Significant Increases in Serum Creatinine by Visit, measured over Baseline, EOT Visit, TOC.

The primary outcome is the number of participants with a clinically significant increase in serum creatinine, assessed at baseline, the End of Treatment (EOT) visit, and the Test of Cure (TOC) visit. EOT/ET occurred on the day therapy stopped or up to 2 days after the last daptomycin dose. TOC/Safety occurred 21 to 28 days after the last dose of daptomycin therapy.

The outcome uses a change threshold that depends on the baseline creatinine category. Elevated baseline serum creatinine is defined as greater than 3.0 mg/dL; a value less than or equal to 3.0 mg/dL is not elevated. For participants with baseline values less than or equal to 3.0 mg/dL, a clinically significant increase is an increase greater than or equal to 0.5 mg/dL. For those with baseline values greater than 3.0 mg/dL, the threshold is an increase greater than or equal to 1.0 mg/dL.

Creatinine is a laboratory measure used to assess kidney function, and a prespecified change threshold makes the outcome more interpretable than an unspecified fluctuation. The baseline-dependent rule accounts for the different starting categories used in this endpoint definition. It does not, by itself, show whether an increase occurred or whether treatment groups differed. The registry record gives the outcome definition and visit timing, but does not report participant counts by visit or a treatment comparison for this outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

In general, randomization assigns participants to treatment groups using a chance-based process. Its purpose is to make systematic baseline differences less likely, so that a comparison of outcomes can be more informative about the assigned treatments. Randomization does not guarantee that groups will be identical, especially in a small study, and it does not remove the need to report baseline characteristics and account for missing outcomes. The registry record describes the study as randomized but does not report the sequence-generation method, allocation concealment, or baseline characteristics needed to examine group balance.

What does double blinding mean for interpretation?

In general, masking is intended to reduce the influence of treatment knowledge on participant experiences, clinical decisions, and outcome assessment. A double-blind designation indicates that the record describes masking at that level, but the registry record does not specify who was masked or how masking was maintained. Masking is not a substitute for clear outcome definitions or a prespecified analysis. For this trial, the primary outcome has an explicit threshold definition; the record does not provide the analysis method used to compare groups.

How should a binary outcome be understood?

The primary outcome is reported as the number of participants meeting a definition of clinically significant creatinine increase. This is a binary classification at a given assessment: a participant either meets the defined threshold or does not. Counts can describe how often the event was recorded, but comparative interpretation usually also needs denominators, an effect measure, and an account of uncertainty. The registry record identifies a Safety Population for this outcome and provides no inferential analysis. It does not report a single primary comparison, so no effect estimate or uncertainty interval can be interpreted from the outcome description alone.

In general, a confidence interval expresses the precision of an estimated effect under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while an interval that includes values consistent with no difference may leave the direction or size of an effect uncertain. No confidence interval for the primary outcome is reported in the registry record. A p-value, if reported, would address compatibility with a specified null hypothesis under an analysis model; it would not measure the probability that a treatment works. No p-value for the primary outcome is reported.

Why do the visit definitions matter?

The outcome is assessed at baseline, EOT, and TOC. Baseline is used to determine which creatinine change threshold applies. EOT/ET occurs on the day therapy is stopped or up to 2 days after the last daptomycin dose. TOC/Safety occurs 21 to 28 days after the last dose. These time points describe different stages of assessment. In general, repeated measurements on the same participant are related rather than independent, so an analysis across several visits may need to account for that structure. The registry record does not report whether such a repeated-measures analysis was conducted, or how results at multiple visits were combined or prioritized.

What do the planning assumptions mean?

In general, a sample-size calculation uses assumptions about the effect to detect, the statistical significance level, allocation, and analysis method. The planning description associated with this record specifies a two-sided significance level of 0.05, equal allocation between the arms, and a normal approximation. It describes planning illustrations based on fractions of an observed effect, rather than the trial’s own design. Such illustrations are planning aids: they are not observed power and do not establish that the trial was designed or conducted with a particular power. The registry record does not report a sample-size justification for the trial. Nor does it report the assumptions used in the trial’s own planning or any resulting planned sample size.

In general, calculations based on an observed effect can be sensitive to the effect estimate used. An estimate from a small study may be imprecise, and planning around it does not establish that a future study will reproduce the same effect. A calculated sample size also does not compensate for missing outcome information or incomplete reporting. No numerical planning estimates are included in the registry record’s outcome information, so the size or implications of any planning illustration should not be inferred from the record.

How should adverse-event counts be compared?

Counts of participants affected are descriptive. A formal comparison requires a defined estimand and statistical method, and its interpretation depends on the denominators, how events and participants are counted, and the uncertainty around the estimate. Participants can experience more than one event, so event counts and participant counts are not interchangeable. The registry record lists participants at risk and participants affected for serious and other adverse events but does not report comparative estimates or uncertainty intervals. The listed counts should therefore be read as event summaries, not as a formal test of a difference between groups.

In general, sparse outcomes can produce imprecise estimates, and small changes in counts can have a substantial influence on an estimate. When event counts are low, standard statistical approximations may also be less reliable; the choice of method should reflect the data structure. The record does not report the method used for adverse-event comparisons, and no analysis is listed. These general considerations explain why descriptive counts alone cannot establish the size or precision of a treatment difference.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists two outcome measures: the primary outcome of clinically significant serum-creatinine increases by visit and the secondary outcome of investigator-assessed clinical response at TOC. It does not report a multiplicity strategy, such as a hierarchy of hypotheses or an adjustment for testing several outcomes or visits. Because the primary outcome is described across baseline, EOT, and TOC, the record also does not clarify whether one visit was intended to be decisive or how multiple time points would be handled in inference. No primary comparative analysis is reported.

Missing-data handling is not reported in the registry record. The record does not state how participants without an assessment at a planned visit were handled, whether reasons for missingness were summarized, or whether any sensitivity analyses were performed. In general, missing outcomes can affect a comparison if the probability of missingness differs by treatment group or is related to the outcome. The available outcome definition does not establish how complete the visit data were.

The Safety Population is defined as all patients who received any dose of study medication. The record does not report an analysis population for efficacy or say whether the primary outcome was analyzed according to randomized assignment, treatment received, or another rule. It also does not describe protocol deviations or exclusions from any analysis. Therefore, the population definition for the safety endpoint should not be assumed to describe every analysis population in the study.

11. 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: bacteraemia (10.0%), endocarditis (10.0%), tachycardia (8.3%), gastrointestinal haemorrhage (8.3%), arthritis bacterial (8.3%).

For serious adverse events, the registry record lists 10 participants at risk and 2 affected in the Daptomycin group, and 12 at risk and 5 affected in the Daptomycin Plus Gentamicin group. For other adverse events, it lists 10 at risk and 8 affected in the Daptomycin group, and 12 at risk and 11 affected in the Daptomycin Plus Gentamicin group. These are descriptive group counts. The record does not report a comparative statistical analysis or uncertainty interval for them.

The listed serious adverse event terms are Bacteraemia and Endocarditis, each reported at 10.0%, and Tachycardia, Gastrointestinal haemorrhage, Arthritis bacterial, and Osteomyelitis, each reported at 8.3%. These percentages describe the registry listing; they are not treatment-effect estimates. The record does not provide enough detail to infer how these terms overlap among participants or to interpret each term as a direct comparison between groups. Death counts are not reported in the registry record.

In general, safety counts describe what was observed and do not by themselves establish that treatment caused an event or that one group had greater risk. Interpretation also depends on event definitions, exposure, follow-up, and how recurrent events were counted. The registry record reports an overall median treatment duration of 13.0 days in both groups, but does not provide a formal analysis connecting exposure duration to these events.

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

The record establishes that a randomized, double-blind Phase 4 study was conducted to describe daptomycin with and without initial gentamicin in S. aureus infective endocarditis. It specifies the primary outcome, its threshold rules, and its assessment timing. It also gives selected safety counts and serious adverse event terms. These details help readers understand what the trial set out to assess and what safety information was entered in the registry.

The record does not report a primary treatment comparison, an effect estimate, a confidence interval, or a p-value. It therefore does not establish the direction, size, or precision of any difference in clinically significant serum-creatinine increases. The secondary outcome is identified as investigator assessment of clinical response at TOC, but no analysis for that outcome is reported. The safety counts are likewise descriptive and are not accompanied by comparative estimates or uncertainty measures.

In general, a study’s design and endpoint definitions are not equivalent to its results. Randomization and masking can support a fair comparison when implemented and analyzed appropriately, but the registry record does not provide enough analysis detail to evaluate those steps or quantify treatment effects. Similarly, an event count alone cannot establish whether an event was caused by treatment or whether a difference is statistically or clinically meaningful.

The trial is marked terminated, with enrollment of 24. The reason for termination and its implications for outcome completeness are not reported in the registry record. Termination should therefore not be taken as evidence for or against either regimen. Overall, the posted information permits a description of the trial’s design and selected safety entries, but does not support a conclusion about comparative efficacy or safety.

13. Why This Trial Matters Statistically

This trial is statistically relevant because it illustrates the distinction between an outcome definition and an analyzed treatment effect. The primary endpoint is specified in detail: it counts participants meeting a baseline-dependent creatinine-change threshold at defined visits. Such detail helps readers understand what qualifies as an event. Yet the registry record does not report the corresponding treatment comparison, so the endpoint definition cannot answer whether the groups differed.

The multiple assessment times also matter. Baseline supplies the reference category, while EOT and TOC occur at different points relative to treatment. A reader needs to know whether results are reported for each visit, summarized across visits, or analyzed using a method that accounts for repeated assessments. Those analysis details are not reported in the registry record. Without them, even a clearly defined endpoint may remain difficult to interpret comparatively.

The safety listings provide another useful statistical lesson: counts are informative descriptions but do not replace an effect estimate and its uncertainty. The record lists affected participants and participants at risk for serious and other adverse events, but gives no formal comparison. This distinction is important when interpreting safety data, particularly when the registry record does not report an analysis method or uncertainty interval.

Finally, the trial’s terminated status and enrollment of 24 make transparent reporting of outcome completeness and analysis especially important. The reason for termination, the handling of missing data, and the sample-size justification are not reported in the registry record. Their absence limits assessment of how much weight to place on the recorded outcome information. The record consequently demonstrates why statistical interpretation depends not only on design labels and endpoint definitions, but also on complete reporting of comparisons, precision, and analysis decisions.

14. 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 does not report a single primary comparison for the serum-creatinine outcome, nor participant counts at the listed assessment visits. It gives no effect estimate, confidence interval, or p-value for the primary endpoint. As a result, the endpoint definition cannot be translated into a comparative result from this record.

The reason for the terminated status is not reported in the registry record. The record also does not state whether termination affected recruitment, follow-up, outcome availability, or analysis. Enrollment is listed as 24, but no sample-size justification is reported. The planning description is an illustration based on an observed effect and specified assumptions; it is not a report of the trial’s original design justification or observed power.

The record identifies a Safety Population but does not provide an efficacy analysis population, a missing-data strategy, or details of exclusions and protocol deviations. It does not report how results across baseline, EOT, and TOC were handled statistically. Multiplicity procedures and interim analyses are not reported in the registry record. The allocation process and practical details of masking are also not described.

The adverse-event entries are limited to selected counts and terms. The registry record does not report comparative estimates, uncertainty intervals, or the statistical method for safety analyses. Death counts are not reported. The event listings should not be used to infer causation, a formal difference between groups, or the full safety profile. These gaps mean that the available record supports a description of the registered trial and selected safety information, rather than a complete evaluation of its efficacy or safety results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 4 Efficacy and Safety Study of Cubicin® With and Without Combination Therapy in S. Aureus Infective Endocarditis (SAIE) — NCT00638157.
• Registry record last updated 2021-02-02; status last verified 2021-01.
• Results first posted 2013-05-22.
• 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.

18. Record Summary

NCT00638157 is a Phase 4, multicenter, randomized, double-blind, parallel-group study of daptomycin alone versus daptomycin with initial gentamicin for S. aureus infective endocarditis. The arm descriptions specify right-sided disease. Enrollment is recorded as 24, and the status is terminated. The registry record lists clinically significant serum-creatinine increases by visit as the primary outcome and investigator-assessed clinical response at TOC as a secondary outcome.

The primary outcome definition uses baseline creatinine categories and specifies assessments at baseline, EOT, and TOC. The registry record does not report a single primary comparison or an analysis for the listed outcomes. It provides descriptive counts for serious and other adverse events, but no comparative estimates or uncertainty intervals. The reason for termination, missing-data methods, sample-size justification, and statistical analysis plan are not reported in the registry record. Accordingly, the record describes the trial design and outcome definitions but does not establish comparative efficacy or safety.