Responses to Rabies Vaccine in Adults With or Without Antibiotics: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Responses to Rabies Vaccine in Adults With or Without Antibiotics (NCT03557008), a randomized phase 4 study. The primary outcome is Antibody Titers.

2. Clinical Question

The registry frames the question around whether antibiotic use changes the immune response after rabies vaccination. The endpoint is a laboratory measure of antibody response, not a direct measure of clinical protection. The posted result compares group averages at the stated follow-up time; it does not describe the entire course of antibody response from vaccination through Day 28.

The study is randomized, but the registry record also states that masking was none. The result should therefore be read as a comparison of the observed Day 28 titers in the reported analysis population, alongside the design and reporting details available in the record. The record does not report additional endpoint analyses or a separate clinical outcome for vaccine effectiveness.

3. Trial Design

This is a Phase 4 randomized, parallel-group study sponsored by Emory University. The registry lists enrollment of 37 and a completed status. The recorded study start is 2018-07-05, and the primary completion date is 2022-06-02. The registry describes two groups with 1:1 randomization: rabies vaccine with antibiotics, and rabies vaccine alone.

Participants assigned to the antibiotic group were to receive rabies vaccine together with metronidazole, vancomycin, and neomycin sulfate. The brief summary describes oral antibiotic treatment beginning 3 days before vaccination and ending one day after vaccination, for a total of 5 days. Participants in the comparison group were to receive rabies vaccine without antibiotics. The registry does not report further details about how the randomization sequence was generated or concealed.

The study is listed as unmasked and uses a parallel model. In a parallel-group design, participants are assigned to a group and the groups are compared; each participant contributes to the group to which they were assigned, rather than crossing between study treatments. The outcome reported for the primary endpoint is based on the participants who completed the Day 28 study visit.

The primary outcome is antibody titers at Day 28, reported as a mean and standard deviation in IU/mL. The registry lists two outcome measures and no secondary outcomes posted. Although the record gives the trial's enrollment and the numbers included in the primary outcome groups, it does not report the original sample-size justification, the detailed statistical analysis plan, interim analyses, or additional design details such as stratification. Those elements should not be inferred from the observed results.

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: This analysis includes participants who completed the Day 28 study visit.

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 Antibody Titers, measured over Day 28.

The primary endpoint is rabies-specific antibody titer at Day 28, measured in blood and reported in IU/mL. The registry describes measurement of rabies-specific Immunoglobulin G (IgG) endpoint titer by ELISA. It defines the endpoint titer as the reciprocal of the highest plasma dilution that produces a reading above a cutoff. The cutoff is based on the average plus 3 times the standard deviation of the reading from a 1:160 dilution of baseline plasma.

This endpoint is used to quantify an antibody response after vaccination. A numerical laboratory measure allows the study to compare the average response in the antibiotic and vaccine-only groups at a specified follow-up visit. Reporting the mean alongside the standard deviation also conveys how much participants’ titers varied within each group.

The endpoint is a biomarker measured at one follow-up time, not a direct assessment of whether participants were protected from rabies or of vaccine effectiveness in clinical use. The registry record does not report a clinical protection endpoint, a threshold interpretation for individual participants, or results at additional time points. The primary analysis population includes participants who completed the Day 28 visit, so the reported means describe that population rather than necessarily all randomized participants.

7. Results Posted in the Registry

• Rabies Vaccine: mean 805.64 versus 217.39 on control; difference 588.25 (95% CI 91.14 to 1,085), standardized effect d = 0.84; z-test p = 0.020.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: antibody titers are measured on a numerical scale and summarized by a mean and standard deviation for each group. The mean describes the arithmetic average of the measurements. The standard deviation describes their spread around that average. A mean comparison is an intuitive way to summarize a difference between two groups, but it does not show every feature of the underlying distributions. When measurements are highly variable or skewed, group means and standard deviations may not fully convey the pattern in the data.

What does the mean difference represent?

The posted comparison is a difference in group means. It reports 588.2 IU/mL, comparing the vaccine-only group mean of 805.6 IU/mL with the antibiotics group mean of 217.4 IU/mL. The positive direction corresponds to the higher average in the vaccine-only group. This is an absolute difference on the antibody-titer scale, not a percentage change or a ratio.

The comparison also reports a standardized effect size, d = 0.836. A standardized effect expresses a difference in relation to a pooled estimate of variability, which can help describe the magnitude on a scale that is less tied to the original measurement units. It does not replace the original-unit mean difference, and it does not establish clinical importance. The record does not report a clinical threshold against which either measure could be judged.

Why report standard deviations?

Standard deviations describe variability among participants in each group. The reported values are 263.0 IU/mL for the antibiotics group and 943.9 IU/mL for the vaccine-only group. The variability is large, especially in relation to the corresponding mean in the vaccine-only group. When dispersion differs between groups, a pooled-variance approach can be less representative of the group-specific uncertainty than methods that allow separate variances. The registry record does not identify the detailed model or variance assumptions used for a sponsor analysis.

Over-dispersion is a general concern when observed measurements vary more than a simple model would anticipate. For continuous data, substantial spread or a skewed distribution can make a normal approximation less reliable, particularly in small samples. This is a general statistical consideration, not a claim that a particular assumption failed in this trial. The registry record does not provide individual titers, distribution plots, a normality assessment, or a model diagnostic with which to assess that issue directly.

How should the confidence interval be understood?

The confidence interval is 91.14 to 1085.0 IU/mL for the reported mean difference. In general, a confidence interval describes the uncertainty around an estimate under the statistical method used. It communicates a range of estimates compatible with the data and method, rather than a guarantee that the true value lies inside that particular interval. A wider interval indicates less precision than a narrower interval on the same scale. Here the interval spans a broad range, so the estimate of the difference’s size is imprecise even though the interval is above zero.

The registry record does not describe the confidence-interval construction method or any adjustment to it. The posted comparison gives an unadjusted p-value of 0.02. In general, a p-value measures how unusual data at least as incompatible with a null model would be if that model and the analysis assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the probability that the result is due to chance. The p-value does not convey the size or clinical meaning of the group difference; those require attention to the estimate, interval, endpoint, and context.

What is known about the analysis?

The displayed comparison is an unadjusted group comparison based on the posted summary statistics. Recalculated comparisons of this kind are simple unadjusted re-calculations from the reported summaries, rather than evidence of a more elaborate trial model. The registry record does not report covariate adjustment, an analysis model, transformations, robust standard errors, or a prespecified analysis plan. It also does not report whether the comparison was the sponsor’s primary inferential analysis. The posted comparison should therefore be read with that limited methodological detail in mind.

Randomization is intended, in general, to make treatment groups comparable on average, including for characteristics not measured by investigators. It does not guarantee that small groups will be balanced on every characteristic, and the registry record does not report baseline balance information for this outcome. The study is listed as unmasked, so participants and investigators were not recorded as blinded. That fact is relevant to understanding the design, although the endpoint itself is a laboratory measurement.

Sample-size calculations and power are also distinct from the observed comparison. A planning calculation asks how many participants may be needed under stated assumptions to detect a target effect with a chosen probability. It is not a measure of the probability that the observed result is true. The trial’s own original sample-size assumptions and justification are not reported in the registry record. Any displayed planning illustrations should be interpreted only under their stated assumptions, not as evidence that the trial was designed around the observed difference.

10. Confidence Intervals and Precision

The mean difference is 588.2 IU/mL, and its confidence interval ranges from 91.14 to 1085.0 IU/mL. This interval indicates meaningful uncertainty about the magnitude of the difference. The full range remains above zero, but its breadth means that the data are compatible with a range of positive differences, from a more modest difference to a much larger one, under the method used for the interval. The point estimate alone does not capture this uncertainty.

Precision is affected by the amount of information in the analysis and the variability of the outcome. The endpoint analysis includes 14 participants in the antibiotics group and 15 in the vaccine-only group. The reported standard deviations, 263.0 IU/mL and 943.9 IU/mL respectively, show substantial within-group variation, especially in the vaccine-only group. With considerable variation, averages can be uncertain even when a numerical difference is observed.

In general, a confidence interval is a way to express uncertainty around an estimate under stated statistical assumptions. It should not be interpreted as a guarantee that the true difference lies within its endpoints, nor does it describe the range of individual participants’ titers. The registry record does not report the interval method, the individual data, or analyses that would show how sensitive the estimate is to distributional assumptions or missing outcomes.

The unadjusted p-value is 0.02, but a p-value and a confidence interval answer related, not identical, questions. The p-value does not say whether the estimated difference is precise or clinically important. The interval helps convey uncertainty in the size of the difference, while clinical meaning would require an appropriate outcome interpretation that is not reported in the registry record.

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 justification. They are stated as participants per arm for the continuous outcome, not as total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; each scenario uses the stated fraction of the observed effect as the effect to detect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the participants per arm estimated to provide an 80% probability of detecting the chosen effect under those assumptions if that effect is the true one. The 90% power column gives the corresponding participants per arm for a 90% probability under the same type of assumptions. These are planning probabilities conditional on the assumed effect and statistical model; they are not probabilities that the study result is correct.

For planning 100% of the observed effect, the figures are 23 participants per arm for 80% power and 31 participants per arm for 90% power. For planning 75% of the observed effect, they are 40 and 54 participants per arm, respectively. For planning 50% of the observed effect, they are 90 and 121 participants per arm, respectively. Smaller effects require more participants because they are harder to distinguish from random variation under the same assumptions.

These figures are illustrations rather than a reconstruction of the trial’s design process, and this is not observed power. Observed power is not a useful substitute for interpreting the estimated difference and its confidence interval. The original assumptions and justification 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 588.250; pooled standard deviation σ = 703.722.
2. n = 2 × (1.96 + 0.842)² × 703.722² / 588.250² = 22.5, rounded up to 23 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 <- 588.25                      # observed difference in means
sigma <- 703.722065725446                     # 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(3557008)
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 = 23 (80% power), 31 (90% power)
 75% of observed effect: n per arm = 40 (80% power), 54 (90% power)
 50% of observed effect: n per arm = 90 (80% power), 121 (90% power)
power.t.test: 23.5 
Simulated power at n = 23 per arm: 0.793 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and no secondary outcomes posted. It does not report a multiplicity strategy, such as how inferential results would be interpreted if several outcomes, time points, or subgroup comparisons were tested. When many comparisons are made, the chance of at least one apparently notable result can increase; this is a general statistical issue, not evidence that a particular unreported analysis was performed in this study. The unadjusted p-value should be read as the posted comparison and not as a value adjusted for a family of tests.

The primary endpoint population consists of participants who completed the Day 28 study visit. The reported outcome counts are 14 for the antibiotics group and 15 for the vaccine-only group, while the registry lists enrollment of 37. The record does not report the reasons that some enrolled participants are not represented in the primary endpoint counts, the amount or pattern of missing outcome data, or whether any outcomes were imputed.

Because the endpoint analysis is defined by visit completion, it is not possible from the registry record to determine how the reported comparison relates to an analysis of all randomized participants. The record does not state whether an intention-to-treat, per-protocol, or other analysis population was used in addition to the Day 28 completer population. It also does not report sensitivity analyses for missing data or describe how withdrawals, protocol deviations, or incomplete visits were handled.

Missing outcome data can affect a group comparison if participants without measurements differ systematically from those with measurements, particularly if those patterns differ between groups. This is a general concern and cannot be assessed from group means alone. The available information does not establish that missingness biased the result, nor does it rule out that possibility. The absence of reported details limits assessment of how robust the endpoint comparison is to the choice of analysis population and missing-data assumptions.

14. 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 non-serious adverse event terms

The registry reports serious adverse events for the safety groups with 19 participants at risk in the antibiotics group and 18 in the vaccine-only group. Serious adverse events affected 0 participants in each group, and deaths were 0 in each group. These are the serious-event and death figures reported in the record; they do not describe the antibody endpoint.

For other adverse events, the registry reports 2 affected participants in the antibiotics group and 1 in the vaccine-only group, with 19 and 18 participants at risk, respectively. The record does not list any serious adverse-event terms. These counts should be read as reported participant counts, not as measures of event severity beyond the categories named in the registry.

Safety counts are descriptive. The record does not provide detailed event definitions, exposure-adjusted rates, timing, attribution, or a statistical comparison for these figures. With the information reported, the counts do not establish whether the groups differ in risk. The registry’s adverse-event figures also do not replace the primary endpoint comparison, which concerns Day 28 antibody titers.

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

The posted results show different Day 28 mean antibody titers in the two randomized groups: 217.4 IU/mL with rabies vaccine and antibiotics, and 805.6 IU/mL with rabies vaccine alone. The unadjusted mean difference is 588.2 IU/mL, with a confidence interval of 91.14 to 1085.0 IU/mL and an unadjusted p-value of 0.02. These statistics describe the measured antibody endpoint among participants who completed the Day 28 visit.

They do not, by themselves, establish what the difference means for protection from rabies, clinical outcomes, or vaccine effectiveness. The registry record reports an antibody measurement but does not report a clinical protection endpoint or a threshold that would translate the group averages into individual protection. It also does not report later antibody measurements, so the result should not be read as a description of response over time beyond the stated Day 28 assessment.

The result does not establish the exact size of a true group difference. The confidence interval is broad, and the standard deviations indicate substantial variation among participants. The p-value is unadjusted and should not be treated as a measure of effect size or clinical importance. The registry record does not report enough detail to assess the effect of missing outcome data, any covariate adjustment, or potential multiplicity.

The randomized design is relevant to interpreting a group comparison, but the endpoint analysis is limited to Day 28 completers and the record does not report the original analysis plan. The findings therefore apply most directly to the posted outcome population, endpoint, and study regimen. They are not a general conclusion about all antibiotics, all vaccines, all populations, or clinical practice. The result is an observation about the laboratory titers recorded in this trial, not medical advice.

16. Why This Trial Matters Statistically

This trial raises a statistical question about comparing a continuous laboratory endpoint between randomized groups when the measurements show substantial variability. The group means differ, but the standard deviations are large, particularly in the vaccine-only group. That combination makes it important to consider both the estimated difference and its uncertainty rather than focusing on the means alone.

The reported confidence interval communicates that the estimated difference is not highly precise. Its breadth reflects uncertainty about the size of the group contrast, even though the interval does not include zero. This is a useful distinction: evidence that a contrast is not centered at zero under a particular analysis does not automatically make its magnitude precise or clinically interpretable.

The endpoint is a biomarker, and its statistical meaning is not identical to a clinical outcome. A rigorous interpretation needs to separate the measured antibody titer from claims about protection or effectiveness, which the registry record does not report. This distinction is important in clinical research because a statistically detectable difference in a laboratory measure may not directly answer a patient-centered or clinical question.

The record also illustrates why analysis populations and missing data matter. The primary endpoint includes Day 28 completers, but the registry does not describe why other enrolled participants are absent from those outcome counts or how missing measurements were handled. Without those details, readers cannot fully assess whether the completer comparison represents all randomized participants. The available results can still be described, but the limits on interpretation should remain visible.

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.

The primary endpoint analysis is limited to participants who completed the Day 28 study visit. Although the registry reports enrollment of 37 and endpoint group counts of 14 and 15, it does not report reasons for non-inclusion in the endpoint analysis, details about missing measurements, or sensitivity analyses. The extent to which the completer results represent all randomized participants cannot be assessed from the registry record.

The groups are small, and the reported titers show substantial variability. The vaccine-only group has a standard deviation of 943.9 IU/mL compared with a mean of 805.6 IU/mL. The record does not include individual-level measurements or distributional summaries that would allow assessment of skew, outliers, or the suitability of a normal approximation for the endpoint comparison.

The registry lists the study as unmasked but does not report additional details about outcome assessment procedures or laboratory masking. It does not report baseline characteristics for the outcome groups, the analysis model, covariate adjustment, the confidence-interval method, or a multiplicity plan. The original sample-size justification and the trial’s own statistical analysis plan are also not reported in the registry record.

The endpoint is an antibody titer at a single stated time point. The registry record does not report a clinical protection outcome, a threshold interpretation for individual titers, or results at other time points. The result therefore has a restricted scope: it describes the posted Day 28 laboratory comparison under this study’s vaccine and antibiotic regimens.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Responses to Rabies Vaccine in Adults With or Without Antibiotics — NCT03557008.
• Registry record last updated 2023-06-08; status last verified 2023-05.
• Results first posted 2023-06-08.
• 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

NCT03557008 is a completed Phase 4 randomized, parallel-group study sponsored by Emory University. It enrolled 37 healthy adults and compared rabies vaccine with metronidazole, vancomycin, and neomycin sulfate against rabies vaccine alone. The study is listed as unmasked, with 1:1 randomization.

The primary endpoint was mean rabies-specific IgG antibody titer at Day 28, measured by ELISA and reported in IU/mL among participants who completed the visit. The posted means were 217.4 in the antibiotics group and 805.6 in the vaccine-only group. The reported unadjusted mean difference was 588.2 IU/mL, with a confidence interval of 91.14 to 1085.0 and p = 0.02.

The registry record does not report the original sample-size justification, detailed analysis plan, missing-data methods, or a clinical protection outcome. The result describes the Day 28 antibody measurements and should not be interpreted as a direct measure of clinical effectiveness.