Intraosseous Vancomycin in Primary Total Hip Arthroplasty - Designing a Protocol: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Intraosseous Vancomycin in Primary Total Hip Arthroplasty - Designing a Protocol (NCT04042233), a randomized phase 4 study. The primary outcome is Systemic Vancomycin Level - Start of Case.

2. Clinical Question

The clinical question is about the distribution of vancomycin concentrations at a specified perioperative time, not about whether either protocol prevents infection or improves other patient outcomes. The registry lists complication outcomes at 30-Day and 90-Day, but the posted secondary results discussed in the record are concentration measures. No conclusion about clinical benefit or harm follows from a concentration difference alone. The study is marked randomized, single masked and parallel, but the registry record does not identify who was masked or describe the randomization procedure.

3. Trial Design

This is a randomized, single-masked, parallel-group phase 4 study with status COMPLETED. It was sponsored by The Methodist Hospital Research Institute. The listed study start date is 2019-12-31, and the primary completion date is 2022-05-25. Registry enrollment is 23. The posted primary endpoint summaries list 10 participants in the IV Group and 10 in the IO Group. These are the recorded counts for that outcome; the registry does not explain the relationship between the overall enrollment figure and the outcome-specific counts.

The comparison was between an experimental intraosseous vancomycin protocol, specified as 500mg in 250 mL NS, and standard IV administration of vancomycin. Both are described as drug interventions. The parallel design means the posted outcome summaries compare separate groups assigned to the respective protocols, rather than reporting a within-person comparison. Allocation is recorded as randomized. The registry does not report the sequence-generation method, allocation concealment, masking details, or whether protocol adherence was assessed.

The primary endpoint is systemic vancomycin level at approximately 10 minutes before incision. Its stated unit is ug/mL, and the registry describes the endpoint as a mean with standard deviation. Secondary outcomes include soft tissue levels at the start and end of the case, femur and acetabulum concentrations, and complications at 30-Day and 90-Day. The registry lists 10 outcome measures and six posted secondary outcomes, but only three secondary concentration outcomes have results in the record. The additional outcomes and analyses are not reported in the registry record.

The study title describes the work as designing a protocol. That title does not establish the detailed protocol rationale, the sample-size justification, or the prespecified statistical analysis. Those details are not reported in the registry record. The record also does not report a trial flow description, baseline participant characteristics, analysis populations, or handling of missing outcome measurements.

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:

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 Systemic Vancomycin Level - Start of Case, measured over approximately 10 minutes before incision.

The primary endpoint is the systemic vancomycin level in blood, measured in ug/mL at approximately 10 minutes before incision. The registry description says the blood level was typically taken approximately 10 minutes before incision. It is summarized as a mean and standard deviation for each group. This endpoint therefore captures a continuous concentration measure at a specified point in the operative timeline.

A systemic concentration is relevant to comparing what is present in the blood under the two administration protocols at that time. In general, measuring concentration can help characterize drug distribution; it is not itself a measure of infection prevention, surgical success, or complications. The posted endpoint can support a comparison of group-average systemic levels, with uncertainty described by the confidence interval. It cannot establish whether a particular concentration is clinically adequate because a target concentration or clinical threshold is not reported in the registry record.

The recorded IV Group mean was 27.98 ug/mL, with standard deviation 13.67, while the IO Group mean and standard deviation were both 0.0. The endpoint timing matters when interpreting these values: they describe the stated pre-incision measurement rather than a general concentration over the entire operation. The registry does not report individual-level results, the assay method, or details about missing or below-detection measurements. Those omissions limit the ability to assess how the concentration summaries were generated and how broadly they represent each group.

7. Results Posted in the Registry

• IO Group: mean 0.00 versus 27.98 on control; difference -27.98 (95% CI -36.45 to -19.51), standardized effect d = -2.89; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Soft Tissue Vancomycin Level - Start of Case

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • IO Group: mean 69.08 versus 63.77 on control; difference 5.31 (95% CI -25.93 to 36.55), standardized effect d = 0.15; z-test p = 0.739.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between IO Group and the control. The interval gives the range of effects that remain compatible with the data.

Femur Vancomycin Concentration Level

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • IO Group: mean 41.45 versus 20.90 on control; difference 20.55 (95% CI -2.04 to 43.14), standardized effect d = 0.80; z-test p = 0.075.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between IO Group and the control. The interval gives the range of effects that remain compatible with the data.

Acetabulum Vancomycin Level

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • IO Group: mean 130.88 versus 67.97 on control; difference 62.91 (95% CI 30.84 to 94.98), standardized effect d = 1.72; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for IO Group than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary concentration results do not all point to the same level of statistical certainty. The soft-tissue start-of-case and femur intervals include zero, while the acetabulum interval lies above zero. The estimates also have different scales and uncertainty, reflecting distinct sites and measurement contexts. Taken together, the pattern is compatible with differences in tissue concentration that may vary by location, but the registry results do not establish a single uniform effect across all tissues.

These tissue findings complement, rather than duplicate, the primary systemic measurement. The primary endpoint concerns blood concentration before incision, while the secondary concentration outcomes concern tissue or operative measurements. A lower systemic concentration at the primary time point can coexist with higher concentrations in a particular tissue measurement; the endpoints describe different compartments and times. The registry record does not report a formal analysis linking systemic levels to tissue levels, so the relationship between these outcomes cannot be quantified from the posted results.

Unadjusted secondary results carry less weight than a prespecified primary comparison because multiple outcomes create more opportunities for a chance finding. The registry lists 10 outcome measures and does not report whether a multiplicity procedure, outcome hierarchy, or secondary-outcome analysis plan was used. The secondary comparisons should therefore be read as descriptive evidence, not as a set of confirmatory claims. The lack of reported analyses for other listed outcomes further limits a comprehensive assessment of the full outcome set.

Clinical complications are among the listed secondary outcomes, but the registry does not post the 30-Day or 90-Day complication results in the outcome summaries. Consequently, the concentration findings should not be interpreted as evidence about complication rates. A more complete reading would require the unreported outcome results and analysis details, including how missing measurements and multiple comparisons were handled.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Soft Tissue Vancomycin Level - Start of Case
• Femur Vancomycin Concentration Level
• Acetabulum Vancomycin Level
• 30-Day Complications
• 90-Day Complications
• Soft Tissue Vancomycin Level - End of Case

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it is a concentration in ug/mL, summarized by a group mean and standard deviation. A mean difference puts the two group averages on the original measurement scale. Here, the comparison is IO Group minus IV Group. A negative value means the recorded IO average is lower than the IV average; it does not by itself establish why the difference occurred or what it means clinically.

What does the confidence interval describe?

In general, a confidence interval is a range of estimates compatible with the observed data under the method used to calculate it. It communicates uncertainty around a point estimate rather than giving a guarantee that the true effect lies inside the particular interval. The primary interval, -36.45 to -19.51 ug/mL, is entirely below zero, consistent with a lower IO mean in this unadjusted comparison. Its width also indicates that the exact size of the difference is uncertain. The registry does not report a full statistical analysis plan, so the interval's calculation method beyond the posted comparison is not reported in the registry record.

How should the p-value be read?

In general, a p-value measures how unusual data at least as incompatible with a null comparison would be under a specified statistical model, assuming the null hypothesis and model assumptions. It is not the probability that the null is true, the probability that chance alone caused the result, or a measure of clinical importance. The primary comparison's p-value is <0.001. It accompanies the estimated difference and interval; it should not replace consideration of the magnitude, measurement process, or study limitations. The posted results do not describe adjustments for covariates or multiplicity.

Why does spread matter?

The standard deviation describes variation in observations within a group, whereas the standard error describes uncertainty in an estimated mean. They are not interchangeable. In the IV Group, the primary standard deviation is 13.67; in the IO Group it is 0.0. A group with no recorded spread has a different contribution to the uncertainty calculation from a group with observed variation. The registry does not explain the zero spread, so it is not possible to determine whether it reflects genuinely identical measured values or a data-recording or assay feature. That uncertainty should be kept in view when interpreting the interval and p-value.

In general, over-dispersion occurs when data vary more than a chosen model expects. If over-dispersion is present, a model that assumes less variation may understate uncertainty and make intervals too narrow. This trial's primary endpoint is summarized with means and standard deviations, and the record does not describe a model-based count analysis or report an assessment of over-dispersion. The concept is therefore a general statistical consideration, not a reported finding about this trial.

What is meant by an unadjusted comparison?

The posted comparisons are unadjusted re-calculations from the group summary statistics. They contrast the group means without a reported adjustment for baseline variables or other covariates. Such a comparison can be informative as a summary of the observed groups, but it does not account for potential baseline imbalance. Randomization is recorded, yet the method of randomization and baseline characteristics are not reported in the registry record. No sponsor-reported analyses are listed, so a different adjusted analysis cannot be evaluated from this record.

The calculations assume that the posted summaries accurately represent the observations used for each endpoint. The registry does not report individual measurements, missing-data handling, exclusions, transformations, or an analysis population. Nor does it say how values recorded as zero were treated. Those details can matter for continuous concentration measurements, especially when one group's summary has a zero mean and standard deviation. The result should therefore be read as a comparison of the posted summaries, not as a complete account of the underlying data or analysis process.

Finally, the record lists multiple outcome measures, while the reported comparisons cover the primary concentration and three secondary concentration measures. When several outcomes are examined, chance can produce apparently unusual findings even if no underlying differences exist. In general, multiplicity adjustments or a prespecified hierarchy can help control how multiple comparisons are interpreted. Whether any such approach was planned or used is not reported in the registry record. This matters particularly for interpreting secondary results, which are unadjusted and should be considered exploratory in the absence of more analysis details.

11. Confidence Intervals and Precision

The primary mean difference is -27.98 ug/mL, and its 95% confidence interval extends from -36.45 to -19.51 ug/mL. The interval excludes zero, so the posted data are compatible with a negative mean difference under the method used for the unadjusted calculation. The result's direction is clear in this interval, but its exact magnitude is not. The range represents uncertainty about the difference, not the range of individual participant concentrations.

Precision is affected by the amount of information and variability in the data. The primary endpoint summaries list 10 observations in each group. The IV Group standard deviation is 13.67, while the IO Group standard deviation is 0.0. The registry record does not explain the zero-valued IO summary, which limits assessment of how much the unusual absence of recorded spread affects the estimated uncertainty. Individual-level data and the measurement or detection details are not reported in the registry record.

The secondary intervals illustrate that precision differs by endpoint. For soft-tissue level at the start of case, the interval ranges from -25.93 to 36.55 ug/mL and includes zero. For femur concentration, the interval ranges from -2.039 to 43.14 ug/mL and also includes zero. For acetabulum concentration, the interval ranges from 30.84 to 94.98 ug/mL and lies above zero. These intervals are unadjusted, and the endpoints are not interchangeable: each concerns a different tissue or measurement time.

A confidence interval does not address all uncertainty. It does not resolve questions about measurement methods, missing outcomes, participant selection, protocol adherence, clinical relevance, or multiple comparisons. The registry does not report enough detail to evaluate those matters fully. Thus, the intervals describe statistical precision for the posted comparisons, while interpretation of the broader trial result remains constrained by the record's omissions.

12. 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 planning figures are illustrations based on the observed effect, not the trial's original design assumptions. The calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The figures give participants per arm for 80% power and participants per arm for 90% power; they are not total participant counts. The original trial's sample-size assumptions and justification are not reported in the registry record.

In general, power is the chance that a study will detect an effect of a specified size under the assumptions used for planning. The 80% power column gives an illustrative per-arm count for detecting the stated effect with 80% power under those assumptions. The 90% power column does the same for 90% power. Higher planned power generally requires more participants when other assumptions are held constant. These planning values are not observed power.

The rows consider 100%, 75% and 50% of the observed effect. The smaller the effect the calculation is designed to detect, the more participants per arm are indicated. This is because a smaller difference is harder to distinguish from random variation than a larger difference, assuming the other planning inputs remain the same. These are illustrations tied to the observed effect and the stated calculation assumptions; they are not evidence that the trial was originally designed to achieve those targets.

These planning counts also depend on assumptions that may not hold in a future study, including the variability and shape of the outcome distribution. The unusual zero spread in the IO primary summary is one reason to avoid treating an observed-effect calculation as a dependable design recommendation without further information. The registry record does not report alternative variance assumptions, an allowance for missing data, or the study's original power calculation.

13. 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -27.980; pooled standard deviation σ = 9.666.
2. n = 2 × (1.96 + 0.842)² × 9.666² / -27.980² = 1.9, rounded up to 2 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
delta <- -27.98                      # observed difference in means
sigma <- 9.6661496988201                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4042233)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 2 (80% power), 3 (90% power)
 75% of observed effect: n per arm = 4 (80% power), 5 (90% power)
 50% of observed effect: n per arm = 8 (80% power), 11 (90% power)
power.t.test: 3.2 
Simulated power at n = 2 per arm: 0.376 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes, including the primary systemic level, several tissue concentration measures, complications at 30-Day and 90-Day, and a soft-tissue level at the end of case. Examining multiple outcomes raises a multiplicity issue: even when each comparison is tested at a conventional threshold, the chance of observing at least one apparently unusual result can increase across a set of tests. In general, prespecified outcome hierarchies or statistical adjustments can address this concern. Whether such methods were planned or used is not reported in the registry record.

The record lists 10 outcome measures and reports three secondary concentration comparisons, but it does not provide a complete analysis plan or explain why only some listed measures have posted results. The registry reports no analyses. Therefore, the posted unadjusted comparisons cannot be interpreted as a documented multiplicity-controlled set of tests. The primary endpoint remains the designated principal comparison in the record, but the absence of a reported plan means the role of the secondary outcomes in the study's inferential strategy is unclear.

Missing-data handling is not reported in the registry record. The outcome summaries give group counts for the primary and posted secondary concentration endpoints, but do not describe whether any observations were missing, excluded, or unavailable for particular measures. The record does not report imputation, complete-case analysis, or sensitivity analyses. The listed enrollment is 23, while the primary endpoint summaries list 10 per group; the record does not explain the distinction, and no inference about participant flow should be drawn from those figures alone.

Analysis populations are also not reported in the registry record. It is not stated whether the reported comparisons use all randomized participants, participants who received the assigned protocol, or another defined population. The registry records random allocation but does not describe protocol adherence, crossovers, or exclusions. These omissions make it difficult to evaluate whether the estimates preserve the intended randomized comparison or how robust they may be to missingness and analysis choices.

These are reporting limitations, not evidence that a particular method was or was not used outside the registry record. Without details on multiplicity, missing data and analysis populations, the safest interpretation is to treat the posted estimates as unadjusted summaries with uncertainty, rather than as a complete inferential account of the trial.

15. Safety Results

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

Deaths

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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (10.0%), rectal bleeding (10.0%).

The registry reports serious adverse events for 10 participants at risk in each group. Serious events affected 2 in the IV Group and 0 in the IO Group. Other adverse events affected 1 in the IV Group and 0 in the IO Group. Deaths are recorded as 0 in both groups. These counts describe the posted safety record; they do not establish that the protocols differ in safety.

The registry's listed serious-event terms are Fall and Rectal Bleeding, each recorded as 10.0%. The record does not provide enough detail in the safety summary to connect those terms to individual participants, describe severity or timing, or assess attribution to the study protocol. It also does not report a comparative statistical analysis for adverse events.

Safety counts from small groups can be unstable and should be interpreted in context. Zero recorded events in a group does not establish that the underlying risk is zero. The registry record does not describe how adverse events were collected, the period of safety follow-up, or whether all participants completed that follow-up. These counts are therefore descriptive and should not be used alone to make a comparative safety conclusion.

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

The primary result describes a difference in mean systemic vancomycin concentration at the specified pre-incision measurement. The IO Group's posted mean was 0.0 ug/mL and the IV Group's was 27.98 ug/mL; the unadjusted mean difference was -27.98 ug/mL, with a 95% confidence interval from -36.45 to -19.51. This is evidence about a recorded concentration at a particular time, not a direct measure of infection prevention or treatment success.

The result does not show whether the concentration in either group was clinically adequate. The registry does not report a target concentration or threshold linked to clinical outcomes. Nor does it report a formal relationship between systemic levels, tissue levels and complications. The secondary concentration results concern different sites, and complications at 30-Day and 90-Day are listed but do not have posted results in the record.

The zero mean and standard deviation in the IO primary summary deserve particular caution. The registry does not explain whether these values are actual measurements, reflect a detection limit, or result from another recording convention. Without that information, the observed summary cannot be interpreted as proof that systemic vancomycin was absent. The data also do not describe the concentration profile outside the recorded measurement time.

Randomized allocation is recorded, but details needed to assess execution and analysis are not reported. Baseline characteristics, masking identity, allocation procedures, missing-data handling and analysis populations are not reported in the registry record. The posted comparisons are unadjusted calculations from group summaries, and the registry lists no analyses. These limits mean the statistics characterize the reported summaries without answering every question about how the groups came to differ.

In general, a statistically clear difference on a laboratory endpoint need not imply a clinically meaningful advantage. Clinical meaning depends on how the measurement relates to patient outcomes, what values are considered relevant, and the quality and completeness of the evidence. Those connections are not established by the posted concentration results. The trial record therefore supports a narrow description of measured levels and their uncertainty, not advice about which protocol should be used or a conclusion that one protocol is clinically superior.

17. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between systemic exposure and concentration measured at operative tissue sites. The endpoints are related to vancomycin measurement but are not identical outcomes. A group contrast in blood before incision and a contrast in tissue during the case answer different questions. Keeping those measures separate prevents a single result from being generalized to every biological compartment or to clinical outcomes.

The primary summary also illustrates why data characteristics matter alongside a p-value. The IO Group has a reported mean and standard deviation of 0.0, while the IV Group has a nonzero mean and spread. A strongly separated summary can yield a narrow inferential conclusion about the direction of the difference under the calculation used, yet still leave important questions about measurement and data recording unresolved. Statistical evidence cannot explain the origin of a zero-valued summary without supporting information about the assay and observations.

The record also makes the distinction between a trial's actual design assumptions and retrospective planning illustrations important. Sample-size illustrations based on observed effects can show how a smaller target difference would require more participants under specified assumptions. They do not tell readers what assumptions guided the original study, and they do not turn a small trial into a definitive assessment of all outcomes.

Finally, the unadjusted secondary results and missing complication results underscore the need for transparent prespecification and complete reporting when multiple outcomes are examined. Clear reporting of outcome definitions, analysis populations, missing data, multiplicity procedures and measurement methods would make the estimates easier to interpret and reproduce. The record's narrow concentration findings are statistically informative within their stated scope, while also showing why effect estimates need clinical context and methodological detail.

18. 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.

A key trial-specific limitation is the unexplained zero mean and zero standard deviation for the IO Group's primary systemic measurement. The registry does not state whether zero denotes a measured concentration, a value below detection, or a coding convention. Because that feature strongly shapes the contrast with the IV Group, the absence of assay and data-handling details limits interpretation of the primary estimate.

The primary endpoint summaries list 10 participants in each group, while registry enrollment is 23. The record does not explain the outcome-specific counts or provide participant flow. It is therefore not possible to determine from the registry whether the difference reflects missing outcome data, other analysis choices, or another reason. Missingness and exclusion details are not reported in the registry record.

There is also limited information about trial conduct. The record marks the study randomized and single masked, but does not say who was masked, how randomization was implemented, or whether the assigned administration protocols were followed. Baseline characteristics and analysis populations are not reported. These omissions limit evaluation of comparability and of whether the posted estimates represent the intended randomized groups.

The primary outcome is a concentration at a single stated time point, and the registry does not report an assay method or a clinical target. Tissue concentration results are available for only some listed secondary outcomes, and complications at 30-Day and 90-Day are not reported in the posted results. The concentration findings therefore cannot establish patient-level clinical effects.

Finally, no sponsor-reported analyses are listed, and multiplicity handling is not reported. The posted secondary comparisons are unadjusted, with several listed outcomes lacking results. The trial's original sample-size rationale, interim analyses and full statistical plan are not reported in the registry record. Together, these gaps limit assessment of both the precision and the completeness of the trial's evidence.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Intraosseous Vancomycin in Primary Total Hip Arthroplasty - Designing a Protocol — NCT04042233.
• Registry record last updated 2025-03-13; status last verified 2025-03.
• Results first posted 2025-03-13.
• 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.

22. Record Summary

NCT04042233 is a completed randomized, single-masked, parallel-group phase 4 study sponsored by The Methodist Hospital Research Institute. It compared an intraosseous vancomycin protocol, specified as 500mg in 250 mL NS, with standard IV vancomycin administration in primary total hip arthroplasty patients. Registry enrollment is 23.

The primary endpoint was systemic vancomycin level at approximately 10 minutes before incision. The posted means were 27.98 ug/mL for IV and 0.0 ug/mL for IO, with an unadjusted mean difference of -27.98 and a 95% confidence interval from -36.45 to -19.51. Three secondary concentration comparisons are posted, with varied estimates and uncertainty. The registry does not report analyses for the listed complication outcomes.

The record does not report the full statistical plan, missing-data handling, analysis populations, measurement details, or an explanation for the zero-valued IO primary summary. The posted findings should therefore be read as concentration comparisons with important interpretive limitations, not as conclusions about clinical benefit or comparative safety.