Safety and Effectiveness of BPL HRIG With Active Rabies Vaccine in Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Effectiveness of BPL HRIG With Active Rabies Vaccine in Healthy Subjects (NCT03264157), a randomized phase 2, phase 3 study. The primary outcome is Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL.

2. Clinical Question

3. Trial Design

This was a prospective, randomized, double-blind, parallel-group, non-inferiority Phase II/III study in healthy subjects. The registry record lists Bio Products Laboratory as the sponsor and the study status as completed. The recorded study start was 2017-12-08, and primary completion was 2018-03-02. Enrollment was 162.

The study compared BPL HRIG with comparator HyperRab. Both arm descriptions specify HRIG at 20 IU/kg with active rabies vaccine, RabAvert. Random allocation and double masking are stated in the registry record. The record does not describe the randomization sequence, allocation concealment, masking procedures, or whether masking was assessed.

The primary outcome was the proportion of subjects with anti-rabies antibody titer of ≥0.5 IU/mL at Day 14. Its stated population was the primary pharmacokinetic population: subjects receiving the full dose of either HRIG product and the first 3 doses of active rabies vaccine on Days 0, 3, 7, with a Day 14 pharmacokinetic sample taken. The registry record also lists secondary measures involving AUC0-7d, RVNA geometric mean titers at specified visits, and proportions reaching antibody thresholds by visit.

The record identifies a Farrington and Manning test for the sponsor's non-inferiority analysis. It does not report the planned sample-size justification, the full statistical analysis plan, or whether interim analyses were conducted. Those details cannot be inferred from the design label or the enrollment figure.

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

Analysis population for the primary outcome, as defined in the registry: Primary PK population (all subjects who receive the full dose of BPL HRIG or comparator HRIG and the first 3 doses of active rabies vaccine on Days 0, 3, 7 and for whom the PK sample at Day 14 is taken).

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 Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL, measured over Day 14.

The primary endpoint measures whether a subject's anti-rabies antibody titer reached the stated threshold of ≥0.5 IU/mL at Day 14. It is a binary outcome: each subject either meets the threshold at that visit or does not. The registry record presents the endpoint as a count of participants and describes a non-inferiority question using a margin of 10%.

In general, a threshold endpoint turns a measured quantity, such as an antibody titer, into a responder classification. That can make the comparison easier to interpret as the proportion reaching a prespecified level, but it also discards information about how far individual measurements lie above or below the threshold. The endpoint is not itself a measure of clinical rabies cases; the registry record describes antibody titers in healthy subjects during simulated post-exposure prophylaxis.

Day 14 is the stated assessment time for the primary endpoint. The primary population definition requires the specified treatment and vaccine doses and a Day 14 pharmacokinetic sample. This population definition matters because the reported proportion applies to that analysis population, rather than automatically representing every enrolled subject. The registry record does not report further details about handling subjects without a Day 14 sample or about other missing endpoint measurements.

The registry record does not give a clinical explanation for selecting the threshold or report evidence establishing how this threshold relates to clinical outcomes. The endpoint should therefore be interpreted as the recorded antibody-response measure and not as a direct demonstration of protection from disease.

7. Results Posted in the Registry

• BPL HRIG + RabAvert: 100.0% (73/73) versus 97.3% (72/74) on control; risk difference 2.7 percentage points (95% CI -1.0 to 6.4), risk ratio 1.03 (0.99–1.07); unadjusted two-proportion z-test p = 0.157.

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help define what a result estimates and what uncertainty it carries. For this endpoint, the registry record presents a binary response at Day 14: whether each participant had an anti-rabies antibody titer of ≥0.5 IU/mL. The posted arm summaries give response counts and denominators, and the unadjusted recalculation expresses the arm comparison as a risk difference.

What does a risk difference represent?

In general, a risk difference subtracts one group's event proportion from the other group's event proportion. Here, the recalculation is oriented as BPL HRIG + RabAvert relative to Comparator HyperRab + RabAvert. The reported estimate is 0.027. A positive estimate means the observed proportion was higher in the BPL arm under that orientation; it does not by itself establish a reliable difference or establish non-inferiority. The risk difference is an absolute measure on the proportion scale, rather than a relative measure.

The unadjusted recalculation uses the posted summary counts. It does not represent an adjusted model or automatically reproduce the sponsor's analysis. The registry also reports a risk ratio in the comparison summary, but the interpretation emphasized for the primary endpoint is the stated risk difference and its confidence interval. No adjustment variables are reported for the recalculation.

How does non-inferiority differ from a conventional difference test?

In general, a non-inferiority analysis evaluates whether the data are compatible with the new or test intervention being worse than the comparator by more than a prespecified margin. The margin defines the largest shortfall that the analysis is designed to rule out. The registry record gives a margin of 10% and identifies a Farrington and Manning test for the sponsor-reported analysis. The registry record does not provide the full test specification, including all details needed to independently reproduce the sponsor's analysis.

A conventional test of no difference addresses a different null hypothesis from a non-inferiority test. Thus, an unadjusted p-value for a difference and a p-value reported for non-inferiority need not answer the same statistical question. The unadjusted recalculation reports p = 0.157; the sponsor analysis reports p < 0.001. Because the discrepancy flag is true, the sponsor's own analysis takes precedence. The two values should not be read as competing estimates from an identical procedure.

What does the Farrington and Manning test contribute?

In general, the Farrington and Manning approach is used for testing non-inferiority or equivalence with binary outcomes and a specified margin. It evaluates the data under a constraint corresponding to the null boundary, rather than simply applying an ordinary test of equal proportions. This makes the test relevant to the sponsor's stated non-inferiority question. The method name alone does not reveal every implementation choice, population rule, or sensitivity analysis, and those details are not reported in the registry record.

The sponsor reports a lower 95% confidence limit of -0.05 and a p-value of 0.001. These statistics belong to the reported non-inferiority analysis. They should be read alongside its margin and test, not as if they were the lower limit and p-value from the unadjusted recalculation. The registry record does not report a corresponding upper confidence limit for that sponsor analysis.

Why can a binary endpoint have limited information?

In general, converting a continuous measurement into a threshold response can simplify communication, because the resulting proportion directly answers how many meet the specified criterion. But participants just above and well above the threshold count alike, as do participants just below and far below it. Continuous antibody measures, such as the listed geometric mean titers, preserve different aspects of the measurement distribution. The registry lists those secondary outcomes but does not provide numerical values for them in the registry record used.

Binary response estimates can also be affected by the number of observations and by how the endpoint is defined. Confidence intervals express uncertainty around an estimate; they do not resolve questions about missing data, eligibility, or whether the endpoint captures a clinically meaningful outcome. The registry record does not report enough detail to assess all such issues.

What do planning illustrations mean?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, significance level, allocation, and statistical model. The stated planning illustrations use the observed effect as their starting point, a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is total events; for other outcomes, it is participants per arm. These are planning illustrations, not observed power and not evidence that the study was designed with those assumptions. The registry record does not report the trial's own sample-size justification.

10. Confidence Intervals and Precision

The unadjusted risk-difference estimate is 0.027, and its reported confidence interval runs from -0.010 to 0.064. In general, a confidence interval describes a range of values compatible with the data and the calculation method under its assumptions. It communicates uncertainty about the estimated effect; it is not a guarantee that the true effect lies within the interval.

The interval includes zero, so the unadjusted recalculation is compatible with no risk difference as well as with values on either side of zero. Its endpoints also show that the estimate is not known with exact precision. The interval belongs to the unadjusted recalculation, not to the sponsor's Farrington and Manning analysis. The sponsor reports a lower 95% confidence limit of -0.05 for its non-inferiority analysis, without a corresponding upper limit in the registry record.

Precision depends on the observed data and the method used to calculate uncertainty. The primary population is specifically defined by treatment receipt, vaccine doses, and availability of the Day 14 sample. The reported precision therefore concerns that analysis context, and should not automatically be generalized to subjects outside the defined population. The registry record does not report details about missing observations or sensitivity analyses that could clarify the effect of alternative population or missing-data choices.

In general, confidence intervals and p-values answer related but different questions. A p-value assesses compatibility with a specified null hypothesis under a particular test; a confidence interval displays a range of effect estimates under a particular method. Here, the unadjusted p-value of 0.157 and its confidence interval describe the recalculation. The sponsor's p-value of 0.001 and lower confidence limit describe the reported non-inferiority analysis. Because the analyses differ and the discrepancy flag is true, the sponsor's own analysis takes precedence for the sponsor-reported non-inferiority result.

11. Analyses Reported by the Sponsor

The sponsor's own analysis is reported as a Farrington and Manning non-inferiority test comparing the two groups. The registry gives a lower 95% confidence limit of -0.05 and p < 0.001, alongside a stated non-inferiority margin of 10%. These figures are the sponsor-reported analysis, not the unadjusted recalculation from the posted summary counts.

The recalculation reports a risk difference of 0.027, a confidence interval from -0.010 to 0.064, and p = 0.157. It is a simple unadjusted recalculation and does not reproduce the sponsor's named test. A difference between the results can arise when the estimand, test procedure, or assumptions differ; the registry record does not report enough detail to identify the source of the discrepancy or independently reconstruct the sponsor's result.

The discrepancy flag is true. Accordingly, the sponsor's own analysis takes precedence when stating the sponsor-reported non-inferiority finding. That precedence does not make the recalculation disappear: it remains a separate descriptive analysis of the posted summary statistics. The two should be presented with their methods and interpretations distinguished, not combined or treated as mutually substitutable. The registry record does not provide the full statistical analysis plan or all implementation details for further reconciliation.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists several secondary outcomes, including AUC0-7d, RVNA geometric mean titers at Days 3, 5, 7 and 14, proportions reaching the ≥0.5 IU/mL threshold by visit, proportions reaching the assay LLOQ by visit, and RVNA geometric mean titers at Days 14, 28, 49 and 140. It lists 5 secondary analyses. The record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or which secondary comparisons were designated confirmatory. Without those details, multiple outcome listings should not be treated as a set of independent confirmations.

In general, when many statistical tests are conducted, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for multiplicity. Different approaches can control error rates or prioritize a prespecified outcome sequence. Which approach was intended for this study is not reported in the registry record. No inference about adjustment can be made solely from the number or names of outcomes.

The primary pharmacokinetic population is defined by receiving the full HRIG dose, receiving the first 3 vaccine doses on Days 0, 3, 7, and having the Day 14 pharmacokinetic sample taken. The registry record does not report how subjects with missing Day 14 samples, incomplete dosing, or other protocol deviations were handled beyond this population definition. It also does not report imputation methods, sensitivity analyses, or a separate intention-to-treat analysis for the primary endpoint.

In general, missing-data handling can matter when endpoint availability is related to participant characteristics or outcomes. The available record does not allow that possibility to be evaluated. Nor does it report whether the sponsor performed interim analyses, or whether any other statistical procedures were prespecified to address repeated looks at the data. These absences limit assessment of the analysis framework; they do not establish that such procedures were or were not used.

13. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each arm as 0 among 81 at risk. It also reports other adverse events for each arm as 19 among 81 at risk, with deaths reported as 0 for each arm. These are the safety figures recorded for BPL HRIG + RabAvert and Comparator HyperRab + RabAvert.

In general, an at-risk count is the denominator used for the corresponding safety summary, and the event count is the number recorded under that category. Serious adverse events and other adverse events are separate categories in the record; the figures should not be combined. The registry lists no top serious adverse event terms. The event counts do not, on their own, describe severity distributions for other adverse events, timing, duration, relatedness assessments, or individual event details.

The safety denominators differ from the primary endpoint denominators, which are reported for the primary pharmacokinetic population. Those summaries answer different questions and should not be substituted for one another. The registry record does not report further details in the information used for this analysis about safety follow-up or how adverse events were coded and assessed.

These figures describe events recorded in this study and do not establish that the products have identical safety profiles. A count of zero serious adverse events in the reported group summaries does not prove that an event cannot occur, and the other-adverse-event counts do not by themselves establish causation. No medical advice or treatment recommendation follows from these summaries.

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

The result concerns a specific antibody-response endpoint: the proportion of subjects reaching an anti-rabies antibody titer of ≥0.5 IU/mL at Day 14. The registry reports an unadjusted risk difference of 0.027 with a confidence interval from -0.010 to 0.064, and separately records the sponsor's Farrington and Manning non-inferiority analysis, with a lower 95% confidence limit of -0.05 and p < 0.001. The stated non-inferiority margin is 10%.

Those analyses should remain distinct. The unadjusted recalculation describes the comparison derived from posted summary statistics, while the sponsor's result is the reported non-inferiority test. Because the discrepancy flag is true, the sponsor's own analysis takes precedence when describing its non-inferiority finding. The registry record does not report enough information to reconstruct the sponsor analysis fully or explain the discrepancy.

The endpoint does not measure clinical rabies cases. The study is described as simulated post-exposure prophylaxis in healthy subjects, and the primary outcome is an antibody threshold at a specified visit. The record does not establish from this endpoint alone whether the antibody response corresponds to clinical protection, nor does it provide results for all listed secondary measures in the registry record used.

In general, non-inferiority is a claim about ruling out a disadvantage larger than a chosen margin under a specified analysis. It is not proof that interventions are identical, and it does not address every potential benefit, harm, or population. The registry record does not report all analysis details needed to assess every assumption or sensitivity of the non-inferiority result.

Accordingly, the posted results can be described as evidence about the recorded Day 14 antibody response and the sponsor's specified non-inferiority analysis. They should not be expanded into a broad claim about all clinical outcomes, all settings, or all participants. The study population, endpoint definition, analysis population, and distinction between sponsor analysis and unadjusted recalculation set the bounds of interpretation.

15. Why This Trial Matters Statistically

This study illustrates why the statistical question must be identified before interpreting a result. The primary endpoint is binary, and the sponsor's stated objective is non-inferiority under a 10% margin. A simple risk difference and an unadjusted test of difference do not necessarily answer the same question as a margin-based non-inferiority test. Reporting the method alongside the estimate is therefore essential to understanding what a p-value is testing.

The record also demonstrates the value of keeping sponsor-reported analyses separate from recalculations based on posted summaries. The recalculation gives an estimate and confidence interval that can be interpreted directly as an unadjusted risk difference. The sponsor reports a Farrington and Manning test and a lower confidence limit for its non-inferiority analysis. Since a discrepancy is flagged, the sponsor's analysis takes precedence for the sponsor-reported conclusion, while the recalculation remains useful as a distinct descriptive comparison.

The endpoint and population definitions matter as much as the model. A threshold at Day 14 conveys the proportion reaching a specified antibody level, while the primary pharmacokinetic population requires specified dosing and a Day 14 sample. This means that the analysis population is not defined simply by enrollment, and that endpoint availability is part of the interpretation.

Finally, the record underscores limits of registry summaries. It lists secondary outcomes and safety counts but does not report a full multiplicity plan, detailed missing-data handling, or the trial's own sample-size justification. Statistical interpretation depends not only on numerical estimates, but also on the prespecified analysis, population, endpoint, and reporting completeness.

16. 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 record supplies a concise outcome summary but does not report the full statistical analysis plan, all implementation details for the Farrington and Manning test, or the sponsor's complete confidence interval. This prevents an independent reconstruction of the sponsor's non-inferiority analysis. A discrepancy is flagged between the sponsor result and the simple unadjusted recalculation, and the source of that discrepancy is not reported in the registry record.

The primary endpoint is a threshold-based antibody measure at Day 14, not a clinical disease outcome. The registry record does not report evidence in this information about the clinical interpretation of the ≥0.5 IU/mL threshold. The binary classification also does not preserve the full distribution of antibody titers, although the record lists geometric mean titers as secondary outcomes without numerical results in the registry record used for this analysis.

The primary population requires full-dose HRIG, the first 3 vaccine doses on Days 0, 3, 7, and a Day 14 pharmacokinetic sample. The registry record does not report how missing samples, incomplete dosing, or other deviations were handled beyond this definition. It does not report sensitivity analyses or clarify how the primary endpoint analysis relates to other possible analysis populations.

The record lists multiple secondary outcomes but does not report a multiplicity strategy or a hierarchy for interpreting them. It also does not report the trial's sample-size justification or whether interim analyses were performed. These omissions constrain assessment of design and analysis choices; they should not be filled in by assumption.

The trial involved healthy subjects and simulated post-exposure prophylaxis, as described in the registry. That context limits what can be inferred about clinical outcomes or other populations. Safety summaries are also limited to the reported event counts and denominators; further details about event timing, relatedness, and follow-up are not reported in the registry record.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Effectiveness of BPL HRIG With Active Rabies Vaccine in Healthy Subjects — NCT03264157.
• Registry record last updated 2020-02-25; status last verified 2020-01.
• Results first posted 2020-02-11.
• 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.

20. Record Summary

NCT03264157 is a completed, randomized, double-blind, parallel-group Phase II/III study sponsored by Bio Products Laboratory. It enrolled healthy subjects and compared BPL HRIG with comparator HyperRab, each described at 20 IU/kg with RabAvert. The recorded start date was 2017-12-08 and primary completion date was 2018-03-02.

The primary endpoint was the proportion with anti-rabies antibody titer of ≥0.5 IU/mL at Day 14 in the defined primary pharmacokinetic population. The registry reports a sponsor non-inferiority analysis using the Farrington and Manning test and separately records an unadjusted recalculation of the risk difference. Because a discrepancy is flagged, the sponsor's own analysis takes precedence for the sponsor-reported non-inferiority result.

Safety summaries report 0 serious adverse events among 81 at risk in each arm, 19 other adverse events among 81 at risk in each arm, and 0 deaths in each arm. Further details on the statistical plan, multiplicity, missing-data handling, and sample-size justification are not reported in the registry record.