Safety and Immunogenicity of Two Intradermal Rabies Vaccine Regimens Administered With and Without Human Rabies Immunoglobulin in Subjects ≥ 1 Years of Age: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of Two Intradermal Rabies Vaccine Regimens Administered With and Without Human Rabies Immunoglobulin in Subjects ≥ 1 Years of Age (NCT02177032), a randomized phase 3 study. The primary outcome is Percentages of Subjects With RVNA Titer >= 0.5 and Vaccine Group Differences ("4-sites, 1-week" to That of "2-sites, TRC" ID PEP Regimen of the PCEC Rabies Vaccine With or Without HRIG Administration).

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, stratified, open-label, multicenter, controlled clinical study with a parallel design. The registry reports enrollment of 885 and a completed status. It lists a start of 2014-06 and primary completion of 2014-10. The sponsor was Novartis. The stated study purpose was to compare immune responses to the new “4-sites, 1-week” intradermal postexposure prophylaxis regimen with the currently recommended “2-sites, TRC” regimen, with or without human rabies immunoglobulin.

The four arm descriptions pair each vaccine schedule with HRIG status: “4-sites, 1-week” without HRIG, “4-sites, 1-week” with HRIG, “2-sites, TRC” without HRIG, and “2-sites, TRC” with HRIG. The vaccine is identified as PCEC rabies vaccine. The arm descriptions specify intradermal administration and state that HRIG was used in adults. Although the study title refers to subjects aged at least 1 years, the registry does not give further age-stratified enrollment details in the primary outcome record.

The primary outcome was assessed in the Per Protocol Set, rather than being described as an analysis of every enrolled participant. That set comprises participants who received the vaccine doses correctly, provided immunogenicity data at the relevant time points, and were not excluded for reasons defined before analysis. The primary endpoint was the percentage with an RVNA titer of at least 0.5 IU/mL at study day 50. The record also lists secondary immunogenicity outcomes at other study days, in children and adults and in adults, as well as solicited adverse events.

The registry does not report further detail about the randomization procedure, allocation concealment, stratification factors, or the sample-size justification. It identifies the study as open label, so masking is listed as none. The record does not establish whether assessors of laboratory outcomes were masked.

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.

Before assignment: All enrolled subjects were included in the trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per Protocol Set (PPS): all subjects who correctly receive the vaccine doses, provided immunogenicity data at the relevant time points and were not excluded due to reasons defined prior to the analysis.

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 Percentages of Subjects With RVNA Titer >= 0.5 and Vaccine Group Differences ("4-sites, 1-week" to That of "2-sites, TRC" ID PEP Regimen of the PCEC Rabies Vaccine With or Without HRIG Administration), measured over Study day 50 (D50).

The primary endpoint is the percentage of participants in the Per Protocol Set whose rabies virus neutralizing antibody (RVNA) titer was at least 0.5 IU/mL at study day 50. RVNA is an antibody measure used in this study to assess immune response after vaccination. The endpoint turns a continuous antibody measurement into a proportion above a prespecified threshold: each participant is counted according to whether the titer meets that threshold.

Comparing these proportions provides a direct way to describe how often participants in each regimen group reached the stated antibody level. It is therefore aligned with the registry’s stated non-inferiority objective, which focuses on whether the percentage meeting the threshold with the new regimen is sufficiently close to the percentage with the currently recommended regimen. A percentage difference and confidence interval describe both the direction of the observed contrast and the uncertainty around it.

The registry reports the threshold as at least 0.5 IU/mL and the assessment time as study day 50. It states that vaccine group differences were calculated assuming a binomial distribution and that the confidence interval for the percentage difference was based on the M-N method. It does not report the non-inferiority margin in the primary outcome record. Without that margin, the numerical difference and its interval can be described, but the record does not establish the prespecified boundary needed to judge the formal non-inferiority criterion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the percentage measure?

The primary outcome is a binary response for each participant: whether the RVNA titer at study day 50 was at least 0.5 IU/mL. The group percentage is the proportion meeting that threshold. General statistical explanation: for a binary endpoint, a binomial model describes the number meeting the criterion relative to the number assessed, while allowing for variation in the observed proportion. The registry states that the group difference was calculated assuming a binomial distribution.

How should the confidence intervals be read?

The reported intervals quantify statistical uncertainty around the estimated group percentages and their difference. General statistical explanation: a confidence interval is a range of values compatible with the data and the method used, not a guarantee that the true value lies within the particular interval. Narrower intervals usually indicate greater precision, while wider intervals indicate more uncertainty. The intervals for the group percentages and the interval for the difference address different quantities and should not be substituted for one another.

For the percentage difference, the registry identifies the M-N method for the confidence interval. General statistical explanation: this is a method for constructing an interval for the difference between two proportions. Its purpose is to quantify uncertainty in the contrast directly, rather than infer that uncertainty solely from separate intervals for each group. The record does not provide additional detail about implementation choices for that method.

What role does Fisher Exact play?

The reported comparison names Fisher Exact and labels the analysis as non-inferiority or equivalence. General statistical explanation: Fisher’s exact test evaluates evidence about association in a two-group comparison of categorical outcomes using the observed counts. It can be useful when the endpoint is binary. The registry does not report a p-value for this comparison, and the method label alone does not supply a significance result or establish the non-inferiority conclusion.

A non-inferiority analysis asks whether the new regimen is not unacceptably worse than its comparator, using a margin defined before examining the results. General statistical explanation: the estimate and its confidence interval are assessed against that margin. The registry record reports the study’s non-inferiority objective and an analysis labeled non-inferiority or equivalence, but the margin is not reported. Consequently, the reported estimate can be interpreted descriptively, while the formal decision rule cannot be reconstructed from the registry information.

Why distinguish the Per Protocol Set?

The primary outcome population is the Per Protocol Set. The registry defines it as participants who correctly received the vaccine doses, provided immunogenicity data at the relevant time points, and were not excluded for reasons defined before analysis. This makes the endpoint estimate conditional on meeting those criteria. General statistical explanation: a per-protocol analysis can describe outcomes among participants who adhered to the study requirements, but exclusions from that set may affect how the result relates to the randomized groups. A complementary intention-to-treat analysis can help assess robustness, but whether such an analysis was performed for this endpoint is not reported in the registry record.

The arm counts reported with the primary result are 357.0 for “4-sites, 1-week” and 350.0 for “2-sites, TRC.” These are the group counts associated with the posted primary endpoint result, not the overall enrollment figure. The record does not explain in this outcome entry how many participants were excluded from the Per Protocol Set or why, nor does it provide missing-data handling details beyond the population definition.

What can be learned from the secondary outcomes?

The registry lists secondary outcomes for geometric mean RVNA concentration, ratios of geometric means, percentages above the same antibody threshold at other study days, adult-specific results, results in children and adults, and solicited local and systemic adverse events. It records 11 posted secondary outcomes, 12 outcome measures, and 17 analyses. These listings show that the study considered outcomes beyond the primary day-50 proportion. The numerical secondary results and any multiplicity procedure are not reported in the primary outcome information.

General statistical explanation: when many outcomes or comparisons are assessed, the chance of at least one apparently unusual result can increase. A prespecified multiplicity strategy may control that risk, or analyses may be treated as exploratory. Whether any such strategy was planned or used is not reported in the registry record. It would therefore be inappropriate to infer that secondary findings were adjusted, or that they were unadjusted, from the outcome list alone.

How should planning illustrations be understood?

General statistical explanation: sample-size calculations describe the number of participants that might be needed under specified assumptions. The planning illustration accompanying the analysis is based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it considers effects stated as fractions of the observed effect. Such figures are planning illustrations, not observed power and not evidence that the trial was designed around those assumptions. The trial’s own sample-size justification is not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry’s reported analysis gives the day-50 protection-rate difference as -1 percentage point, with a 95% confidence interval from -2.4 to 0, and identifies Fisher Exact as the comparison method. It does not report a p-value. These are the sponsor’s posted comparison results in the registry record; the endpoint is defined for the Per Protocol Set and the comparison is labeled non-inferiority or equivalence.

The record does not report a separate recalculated estimate in the primary outcome details. No discrepancy is flagged between the posted analysis and a recalculation in the registry information. The sponsor’s own analysis is therefore the relevant reported result, rather than an alternative estimate presented as a replacement. The interval and difference can be read descriptively, but the non-inferiority margin is not reported. Without that margin, the formal non-inferiority decision cannot be independently verified from the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The primary result is defined for a Per Protocol Set: participants who correctly received vaccine doses, provided immunogenicity data at relevant time points, and were not excluded for reasons defined before analysis. The registry does not report a participant flow for this set in the primary outcome record, the reasons for exclusions, or the number of missing day-50 measurements. It also does not describe an imputation method or other missing-data procedure. These omissions limit assessment of how missing observations and protocol deviations may affect the estimate.

The registry lists 11 posted secondary outcomes, 12 outcome measures, and 17 analyses. These include antibody concentrations, ratios between group geometric mean concentrations, proportions above the RVNA threshold at other study days, age-group analyses, and solicited adverse events. The record does not report whether multiplicity was controlled, which outcomes were designated for confirmatory interpretation, or how secondary analyses were prioritized. Without that information, secondary findings should not be treated as having the same evidential status as the stated primary outcome.

The primary outcome description says the population is the whole study population but specifies the Per Protocol Set for the analysis. It does not report a corresponding intention-to-treat estimate for the primary endpoint. Whether interim analyses were performed, whether any analysis populations were specified beyond those described, and how missing data were addressed are not reported in the registry record. The non-inferiority margin and the sample-size justification are also not reported, preventing a full assessment of the design assumptions and decision framework.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: animal bite (2.2%), appendiceal abscess (1.2%), dengue fever (1.2%), tonsillitis (1.2%), angina unstable (1.1%).

The registry reports serious adverse events and other adverse events in four groups. For serious adverse events, the at-risk and affected counts are 356 and 5 for “4-sites, 1-week” without HRIG; 85 and 1 for the corresponding group with HRIG; 353 and 4 for “2-sites, TRC” without HRIG; and 89 and 2 for the corresponding group with HRIG. For other adverse events, the respective at-risk and affected counts are 356 and 292; 85 and 78; 353 and 298; and 89 and 82.

These counts are descriptive safety summaries. The registry lists Animal Bite at 2.2%, Appendiceal Abscess at 1.2%, Dengue Fever at 1.2%, Tonsillitis at 1.2%, Angina Unstable at 1.1%, and Urinary Tract Infection at 1.1% among the serious-event terms. The record does not specify in this entry how those term percentages relate to the four treatment groups, so they should not be assigned to an individual arm. Death counts are not reported in the registry record.

Event counts alone do not establish whether an event was caused by vaccination. The registry information does not provide event-level timing, severity grading beyond the serious-event category, or a causal assessment for each event. The groups also differ in their reported at-risk counts, so raw counts should not be compared as though group sizes were identical.

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

The primary result describes the observed proportion of participants in the Per Protocol Set who reached the RVNA threshold at study day 50 under each of the two intradermal vaccine schedules. The reported percentages were 99.0% for “4-sites, 1-week” and 100.0% for “2-sites, TRC.” The registry’s estimated difference was -1 percentage point, with a 95% confidence interval from -2.4 to 0. This is evidence about a specific antibody threshold at a specified assessment time in the analysis population defined by the registry.

The result does not by itself establish that the regimens are equivalent or that the new regimen met a non-inferiority criterion. The registry describes non-inferiority as the study objective, but the margin required to assess that objective is not reported. The confidence interval can be interpreted as an estimate of the plausible difference under the stated method, but without the margin it is not possible to determine whether the interval satisfies the study’s intended decision rule.

The result also does not describe every endpoint in the study. The registry lists secondary antibody concentration measures, other assessment days, age-specific outcomes, and adverse events. Numerical results for those outcomes are not included in the primary result. Nor does the primary outcome provide a comprehensive comparison of safety; the serious and other adverse event counts are separate descriptive information.

General statistical explanation: a trial result is not a universal property of a treatment. It is an estimate for the population, regimens, outcome definition, follow-up time, and analysis approach studied. The registry record describes children and adults aged at least 1 years and specifies HRIG use in adults in the arm descriptions. It does not justify extending the result to other populations, schedules, or clinical circumstances. These findings are a statistical description of posted trial data, not individual medical guidance.

14. Why This Trial Matters Statistically

This trial poses a clear statistical comparison between two intradermal rabies vaccine schedules and frames the primary objective as non-inferiority. That design makes the contrast and its uncertainty especially important: a small observed difference is not enough on its own to establish non-inferiority. The margin must be defined and the estimate assessed against it. Because the margin is not reported in the registry record, the posted data support description of the antibody response contrast but not an independent verification of the formal non-inferiority conclusion.

The endpoint is a thresholded antibody response. It is easy to interpret as a percentage meeting a stated level, but it discards information about how far above or below the threshold individual measurements lie. The study’s listed secondary outcomes include geometric mean antibody concentrations, which address antibody level differently, as well as percentages at other study days. The primary day-50 proportion should therefore be understood as one specific view of immunogenicity, not a complete account of all antibody measurements.

The Per Protocol Set is also statistically consequential. It focuses the primary comparison on participants who met the stated dosing and data criteria. The registry does not provide a corresponding intention-to-treat result or detailed information about exclusions and missing observations in the primary outcome record. Readers therefore have limited information for judging how protocol adherence and missing data might influence the result.

Finally, the registry lists multiple secondary outcomes and analyses. Without information about multiplicity handling or which secondary analyses were confirmatory, isolated secondary findings would need cautious interpretation. These features illustrate why a reported point estimate should be read alongside the analysis population, confidence interval, decision margin, and reporting completeness.

15. Limitations

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

The registry record does not report the non-inferiority margin, although non-inferiority is the stated objective. This prevents an independent assessment of whether the reported difference and confidence interval satisfy the prespecified criterion. The record also does not report the sample-size justification, so the basis for the planned enrollment and the assumptions behind it cannot be reviewed.

The primary outcome is analyzed in the Per Protocol Set, and the registry defines the criteria for inclusion. However, the primary result entry does not give a participant flow, reasons for exclusion, missing day-50 measurement counts, or a missing-data method. It does not report a corresponding intention-to-treat result for this endpoint. These gaps restrict assessment of the robustness of the estimate to analysis-population choices and incomplete observations.

The study is listed as open label, with no masking. The registry record does not state whether laboratory assessment was masked. It also does not provide details of randomization procedures, allocation concealment, or stratification factors. These design details are relevant to evaluating conduct and potential bias but cannot be inferred from the broad design labels.

The registry lists several secondary outcomes and analyses but does not report multiplicity handling in the primary outcome information. Numerical results for those secondary outcomes are not presented in the registry record for this comparison. Safety information is limited to at-risk and affected counts and a list of serious-event terms with percentages; the record does not provide causal assessments in this entry. Death counts are not reported in the registry record. Together, these reporting limits call for a focused interpretation of the primary estimate rather than broader conclusions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of Two Intradermal Rabies Vaccine Regimens Administered With and Without Human Rabies Immunoglobulin in Subjects ≥ 1 Years of Age — NCT02177032.
• Registry record last updated 2017-04-07; status last verified 2017-02.
• Results first posted 2017-04-07.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02177032 is a completed Phase 3 randomized, stratified, open-label, multicenter, controlled study with a parallel design. It compared the intradermal PCEC rabies vaccine “4-sites, 1-week” regimen with the “2-sites, TRC” regimen, with and without HRIG. The primary endpoint was the percentage with an RVNA titer of at least 0.5 IU/mL at study day 50 in the Per Protocol Set.

The registry reports 99.0% for “4-sites, 1-week” and 100.0% for “2-sites, TRC,” with a difference of -1 percentage point and a 95% confidence interval from -2.4 to 0. The analysis is labeled non-inferiority or equivalence and uses Fisher Exact. The non-inferiority margin, sample-size justification, missing-data procedures, and multiplicity strategy are not reported in the registry record. The observed result can be described, but the formal non-inferiority criterion cannot be independently assessed from the recorded information.