Study of Daptomycin in Subjects Undergoing Surgery for Osteomyelitis Associated With an Infected Prosthetic Caused by Staphylococci: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Daptomycin in Subjects Undergoing Surgery for Osteomyelitis Associated With an Infected Prosthetic Caused by Staphylococci (NCT00428844), a randomized phase 2 study. The primary outcome is Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L).

2. Clinical Question

The study was designed to investigate safety, efficacy, and pharmacokinetics in people undergoing standard-of-care surgery for an infected prosthetic hip or knee associated with staphylococci. Its primary posted outcome is the number of participants with a specified CPK elevation, measured by the central laboratory. The comparison is between each daptomycin dose group and the comparator group.

The clinical context is a surgically managed prosthetic joint infection. The listed secondary outcomes include overall clinical outcome, microbiological response, notable laboratory abnormalities, and pharmacokinetic measures. Their presence describes the scope of the study, but comparative results for those outcomes are not reported in the registry record. The posted primary result therefore addresses only the specified laboratory safety endpoint.

3. Trial Design

This was a phase 2, randomized, parallel-group study with no masking. The registry record lists enrollment of 75 participants and describes the study as completed. The study start date is 2007-06-26, and the primary completion date is 2010-03-26. The listed groups were daptomycin 6 mg/kg, daptomycin 8 mg/kg, and comparator. The primary outcome is identified for the Safety Population.

Both daptomycin regimens were given every 24 hours as a 30-minute intravenous infusion for 6 weeks, with a permitted variation of one week. The comparator was not a single drug: it could be vancomycin or teicoplanin, or a semi-synthetic penicillin selected from nafcillin, oxacillin, and flucloxacillin. Vancomycin is described as 1 gram every 12 hours by 60-minute infusion, and teicoplanin as 6 mg/kg every 24 hours by 30-minute infusion, also for 6 weeks with a permitted variation of one week. The dosing description for the penicillin options is incomplete in the registry record.

The posted primary result gives denominators of 25 participants for daptomycin 6 mg/kg, 24 for daptomycin 8 mg/kg, and 25 for comparator. These are the denominators attached to the primary endpoint results; they should not be treated as a replacement for the registry’s enrollment figure. Details of the randomization procedure, allocation concealment, site structure, eligibility criteria beyond the stated infection and surgery context, and the trial’s original sample-size justification are not reported in the registry record.

The combination of randomized allocation and no masking matters when interpreting the design. Randomization is intended to support comparable groups, while the absence of masking means treatment assignment was not concealed from participants or study personnel in the usual masked-trial sense. The registry record does not describe additional steps used to limit bias in outcome assessment or care.

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.

Completed Study Drug Treatment

Reasons for not completing this period:

Completed Test of Cure (TOC) Visit

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 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 Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L), measured over From the 3rd day of therapy to 1 week post last dose (approximately week 7).

The primary endpoint counts participants with any creatine phosphokinase (CPK) elevation above 500 U/L. The registry description specifies that the measurement was made by the central laboratory and that the qualifying period ran from Day 3 of therapy through 7 days after the last dose of study medication, identified as Day 7P. The timeframe is described as approximately week 7. This is a binary outcome: each participant either met the stated threshold during the specified period or did not.

CPK is a laboratory measure, and a threshold-based endpoint turns a continuous laboratory result into a count of participants crossing a prespecified level. This can make a safety signal easier to summarize across treatment groups than a long series of individual laboratory measurements. It also means that the endpoint does not describe the size, duration, or clinical consequences of an elevation, nor does it capture every possible safety outcome. The posted result reports counts of participants, not the distribution of CPK values or the severity of elevations.

The choice of a laboratory safety endpoint is consistent with the study’s stated safety focus, but the registry record does not provide a rationale for selecting this threshold or timeframe. The endpoint should be interpreted as a measure of participants meeting this particular laboratory criterion, rather than as a complete account of safety or as a measure of clinical efficacy.

7. Results Posted in the Registry

• Daptomycin 6 mg/kg: 16.0% (4/25) versus 8.0% (2/25) on control; risk difference 8.0 percentage points (95% CI -9.9 to 25.9), risk ratio 2.00 (0.40–9.95); unadjusted two-proportion z-test p = 0.384.
• Daptomycin 8 mg/kg: 20.8% (5/24) versus 8.0% (2/25) on control; risk difference 12.8 percentage points (95% CI -6.6 to 32.3), risk ratio 2.60 (0.56–12.16); unadjusted two-proportion z-test p = 0.199.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is binary because it records whether each participant experienced the defined CPK elevation during the stated monitoring period. For a binary endpoint, the group result can be expressed as an event count alongside the number of participants assessed. The posted counts are 4 of 25 for daptomycin 6 mg/kg, 5 of 24 for daptomycin 8 mg/kg, and 2 of 25 for comparator. These counts are the direct data underlying the comparisons. No additional percentage calculation is needed to understand the basic direction and uncertainty of the posted estimates.

The principal comparative measure reported is the risk difference. In general statistical terms, a risk difference contrasts the event proportions in two groups by subtraction. A value above zero means the event was more frequent in the first named group in the posted comparison; a value below zero means it was less frequent. The reported values are 0.08 for daptomycin 6 mg/kg versus comparator and 0.128 for daptomycin 8 mg/kg versus comparator. These estimates describe the observed contrast, but the confidence intervals show that estimates compatible with either direction remain plausible.

The registry also reports risk ratios and odds ratios. In general, a risk ratio compares the event proportions between groups, while an odds ratio compares the odds of an event. Both are ratio measures, so a value of one corresponds to no contrast on that scale. The posted risk ratio and odds ratio estimates are 2.0 and 2.19 for the 6 mg/kg comparison, and 2.604 and 3.026 for the 8 mg/kg comparison. The associated intervals are wide and include the no-contrast value of one. These measures describe the same binary endpoint using different scales; they do not replace the absolute counts or resolve the uncertainty created by the small denominators.

A confidence interval expresses a range of values compatible with the data under the interval’s statistical assumptions. In general, a wider interval indicates less precision. The risk-difference intervals are -0.099 to 0.259 for daptomycin 6 mg/kg versus comparator and -0.066 to 0.323 for daptomycin 8 mg/kg versus comparator. Both include zero, the value corresponding to no risk difference. The registry record does not identify the method used to construct the confidence intervals, so no particular interval procedure should be assumed.

The reported p values are unadjusted: 0.384 for the 6 mg/kg comparison and 0.199 for the 8 mg/kg comparison. In general, a p value evaluates the observed data against a null hypothesis using a statistical model. It is not an effect size, a measure of clinical relevance, or a probability that the null hypothesis is true. Because the registry record does not report the analysis plan, the test used to obtain these p values and any planned decision threshold are not reported in the registry record.

Randomization is a design feature intended to reduce systematic differences between groups at allocation. It does not guarantee balance in a small trial, and it does not itself resolve uncertainty in the endpoint estimates. The study was unmasked, so treatment assignment was not concealed from participants and study personnel. The record does not report the allocation procedure, concealment methods, or safeguards used for laboratory outcome assessment. The CPK measurement is described as central-laboratory based, which identifies the measurement source but does not supply details about blinding or adjudication.

Over-dispersion is a general concern when observed variation is greater than a model expects. For count outcomes, models that assume a particular variance structure can understate uncertainty if that assumption is not met. This endpoint is posted as participant counts for a binary outcome, and no over-dispersion assessment or model-based analysis is reported in the registry record. It would therefore be inappropriate to infer that an over-dispersion correction was or was not used.

The primary analysis population is identified as the Safety Population. The registry record does not describe the population definition in detail, how participants with missing laboratory measurements were handled, or whether an intention-to-treat analysis was performed. These details matter because exclusions and missing outcomes can affect which participants contribute to a group comparison. The posted denominators should therefore be interpreted as the endpoint-specific denominators, not as proof that every enrolled participant was analyzed.

The record reports no analysis count for the outcomes listed and gives five secondary outcomes. The precise methods for those outcomes are not reported in the registry record. The primary endpoint result can be interpreted on its own as a comparison of observed counts, but the absence of documented analysis methods limits assessment of how the overall set of outcomes was handled.

10. Confidence Intervals and Precision

Precision is limited for the primary comparisons. The confidence interval for the risk difference between daptomycin 6 mg/kg and comparator runs from -0.099 to 0.259. The interval for daptomycin 8 mg/kg versus comparator runs from -0.066 to 0.323. Each interval includes zero, so the posted data are compatible with no risk difference as well as with differences in either direction. The intervals also span a substantial range of possible effects, indicating that the point estimates should not be treated as precise descriptions of the underlying contrast.

The group denominators are 25, 24, and 25, and the event counts are 4, 5, and 2. With a limited number of participants and relatively few observed events, an individual outcome can materially affect the estimated contrast. This is reflected in the wide intervals for the risk ratios and odds ratios as well: the risk ratio intervals are 0.402 to 9.949 and 0.558 to 12.16, while the odds ratio intervals are 0.363 to 13.22 and 0.526 to 17.39. The intervals include the no-contrast value of one.

In general, a confidence interval is not a guarantee that the true effect lies within its bounds. Rather, it communicates uncertainty under the assumptions of the method used. The registry record does not report the interval-construction method or the analysis plan, so the reported intervals should be read as posted, without attributing them to a particular procedure. Precision is distinct from statistical significance and from clinical importance. These data leave considerable uncertainty about the magnitude and direction of the comparative difference in this specific laboratory endpoint.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial’s original design. For the daptomycin 6 mg/kg comparison, planning for 100% of the observed effect gives 258 participants per arm for 80% power and 345 participants per arm for 90% power. Planning for 75% of the observed effect gives 426 participants per arm for 80% power and 570 participants per arm for 90% power. Planning for 50% of the observed effect gives 882 participants per arm for 80% power and 1,181 participants per arm for 90% power.

For the daptomycin 8 mg/kg comparison, planning for 100% of the observed effect gives 117 participants per arm for 80% power and 156 participants per arm for 90% power. Planning for 75% of the observed effect gives 189 participants per arm for 80% power and 252 participants per arm for 90% power. Planning for 50% of the observed effect gives 379 participants per arm for 80% power and 506 participants per arm for 90% power.

These figures are participants per arm, not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The 80% power column gives the planned per-arm size under which the calculation targets an 80% chance of detecting the specified effect under those assumptions. The 90% power column uses a higher target chance. Smaller effects require more participants, as reflected by the larger figures for the smaller fractions. These are planning illustrations, not observed power. The trial’s own original sample-size assumptions are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.080; treatment proportion p₁ = 0.160; average p̄ = 0.120.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4596 = 0.9007.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4561 = 0.3838.
4. n = (0.9007 + 0.3838)² / (0.0800)² = 257.8, rounded up to 258 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.08                          # control proportion
p1 <- 0.16                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(428844)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 258 (80% power), 345 (90% power)
 75% of observed effect: n per arm = 426 (80% power), 570 (90% power)
 50% of observed effect: n per arm = 882 (80% power), 1,181 (90% power)
power.prop.test: 257.8 
Simulated power at n = 258 per arm: 0.806 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists five secondary outcomes in addition to the primary endpoint. They cover notable laboratory abnormalities, overall clinical outcome, microbiological response, and pharmacokinetic measures. The record does not provide comparative estimates for those secondary outcomes, and the analysis count is listed as zero. The listed outcomes therefore indicate the intended breadth of assessment, but do not permit conclusions about their results.

When a study evaluates multiple outcomes or makes multiple comparisons, the chance of a false-positive finding across the set can differ from the chance associated with a single test. General statistical approaches to multiplicity can adjust significance thresholds or otherwise control error rates. Whether any such approach was planned or used is not reported in the registry record. The posted p values for the primary comparisons are described as unadjusted; no correction for multiple comparisons is described.

Missing-data handling is also not reported in the registry record. The primary endpoint is identified for the Safety Population, but the definition of that population, the number of participants with missing CPK measurements, and the handling of missing measurements are not specified. The endpoint-specific denominators are 25, 24, and 25. The registry record does not explain whether any participants were excluded from the Safety Population, whether measurements were unavailable, or how such cases were treated in analysis.

The registry record does not state whether the primary comparisons were adjusted for baseline factors, whether an intention-to-treat population was used for other outcomes, or how analysis populations were defined beyond the Safety Population label. It also does not report a prespecified statistical analysis plan or interim analyses. Those details should not be inferred from the randomized design or from the posted result. The primary finding can be described from the reported counts and estimates, but the broader analysis strategy and its approach to missingness and multiplicity remain unclear.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: urinary tract infection (8.0%), dislocation of joint prosthesis (8.0%), anaphylactic reaction (4.2%), device related infection (4.2%), rhabdomyolysis (4.2%).

The serious adverse event figures count participants affected in each group: 8 of 25 for daptomycin 6 mg/kg, 4 of 24 for daptomycin 8 mg/kg, and 8 of 25 for comparator. The other adverse event figures count 23 of 25, 18 of 24, and 22 of 25 participants, respectively. These are participant counts, not counts of all event episodes, and the registry record does not provide the definitions or follow-up details needed to interpret their full scope.

The listed serious adverse event terms include urinary tract infection and dislocation of joint prosthesis, each reported as 8.0%, and anaphylactic reaction, device related infection, rhabdomyolysis, and deep vein thrombosis, each reported as 4.2%. These entries describe terms and percentages in the record; they do not establish that study treatment caused the events. Death counts are not reported in the registry record. As with the primary laboratory endpoint, group summaries alone do not describe timing, severity, duration, or individual clinical circumstances.

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

The primary result documents that CPK elevations above 500 U/L were observed in each of the three groups during the stated monitoring period. The count was 4 of 25 with daptomycin 6 mg/kg, 5 of 24 with daptomycin 8 mg/kg, and 2 of 25 with comparator. The posted risk-difference estimates are positive for both daptomycin comparisons, but their confidence intervals include zero and extend in both directions. The data therefore do not precisely determine the comparative difference for this endpoint.

This finding does not answer whether the treatments differed in clinical outcome, microbiological response, or pharmacokinetic measures. Although those outcomes are listed as secondary measures, their numerical results are not reported in the registry record. Nor does a count of laboratory threshold crossings establish the cause or clinical consequence of an elevation. The results should be understood as a record of participants meeting a specific laboratory criterion, not as a complete safety assessment.

The trial was randomized and unmasked, and its primary endpoint population is identified as the Safety Population. Important details about the analysis plan, missing measurements, and treatment of multiple outcomes are not reported in the registry record. This limits assessment of how the posted estimates were derived and how they fit into the trial’s full analysis strategy.

The observed counts are small, and the intervals are broad. A point estimate is only one summary of the data; it should be read alongside the event counts and the uncertainty intervals. The unadjusted p values do not measure the size of a difference or the probability that a treatment effect is real. The result does not establish that one regimen is safer or less safe overall, and it does not support medical advice or a treatment recommendation. It describes the posted comparison for one laboratory safety endpoint in this trial.

16. Why This Trial Matters Statistically

This trial illustrates why a result should be read in terms of both its endpoint and its precision. The study’s broad aims included safety, efficacy, and pharmacokinetics, but the primary posted result is a binary laboratory safety measure. That distinction prevents a CPK endpoint from being mistaken for a direct measure of infection control or overall clinical benefit.

The observed group counts are close in absolute terms, but the comparative estimates remain uncertain because the denominators are limited and the confidence intervals are wide. A single point estimate can give a misleading impression of certainty if separated from its interval. Here, each risk-difference interval includes zero and permits effects in either direction. The reported ratio intervals are also broad and include their no-contrast value. Together, these features show how limited information can constrain interpretation even when the study has a randomized design.

The heterogeneous comparator is another statistical consideration. It could involve different antibiotics, and the registry record does not report how many participants received each comparator option. The comparator group therefore represents a regimen category rather than a single treatment exposure in the posted summary. This makes the exact meaning of a group-level contrast dependent on the composition of that category, which is not described.

Finally, the record lists several secondary outcomes without their comparative estimates and does not document key elements of the analysis plan. The available result supports a focused description of the primary endpoint, not a complete statistical account of every study question. The planning illustrations also show that estimates from small studies can imply much larger sample requirements when used to plan a future study, especially when aiming to detect a smaller effect. Those illustrations are not the trial’s original design justification.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations affect interpretation. The primary endpoint is a laboratory threshold crossing, and the record does not provide individual CPK values, the magnitude or duration of elevations, or clinical consequences. It also does not report the rationale for the 500 U/L threshold or for the monitoring window that begins on Day 3 and extends to 7 days after the last dose. The result therefore addresses only whether the criterion was met during that period.

The comparator category combines multiple possible regimens. Vancomycin and teicoplanin dosing are described, and the penicillin options are named, but the penicillin dosing description is incomplete in the registry record. The distribution of participants across comparator options is not reported. The group contrast may consequently reflect a mixture of comparator exposures whose composition cannot be assessed from the posted information.

The primary endpoint denominators are 25, 24, and 25, while enrollment is listed as 75. The registry record does not explain the relationship between enrollment and the endpoint-specific populations, or whether any participants lacked an evaluable CPK measurement. The definition of the Safety Population and missing-data handling are not reported. Randomization details, allocation concealment, baseline group characteristics, and the statistical analysis plan are also not reported in the registry record.

The record lists secondary outcomes but provides no comparative numerical results for them, and it does not document any approach to multiplicity. The trial was unmasked, which may affect conduct or assessment, although the primary outcome is described as measured by a central laboratory. The registry record does not describe blinding of laboratory staff or other safeguards. These limitations do not erase the posted counts, but they restrict the conclusions that can be drawn from them.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study of Daptomycin in Subjects Undergoing Surgery for Osteomyelitis Associated With an Infected Prosthetic Caused by Staphylococci — NCT00428844.
• Registry record last updated 2018-01-31; status last verified 2018-01.
• Results first posted 2011-06-14.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT00428844 is a completed, randomized, unmasked phase 2 parallel-group study of daptomycin 6 mg/kg, daptomycin 8 mg/kg, and a comparator regimen in participants undergoing surgery for staphylococcal infection associated with a prosthetic hip or knee. Enrollment is listed as 75. The primary endpoint counts participants with CPK above 500 U/L from Day 3 through 7 days after the last dose, approximately week 7.

The primary counts are 4 of 25, 5 of 24, and 2 of 25 for the respective groups. The reported risk-difference intervals include zero and are wide, so the comparative estimates are imprecise. Secondary outcomes are listed, but their comparative results and important details of the statistical plan, missing-data handling, and multiplicity approach are not reported in the registry record.