Effect of Antimalarial Drugs to Rabies Vaccine for Post-exposure Prophylaxis.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Antimalarial Drugs to Rabies Vaccine for Post-exposure Prophylaxis. (NCT02564471), a randomized phase 4 study. The primary outcome is Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value.

2. Clinical Question

3. Trial Design

The registry describes a randomized, open-label, parallel-group, Phase 4 trial sponsored by State University of New York - Upstate Medical University. Its status is completed. The recorded start was 2016-11-11, and primary completion was 2018-08. The title describes healthy US adults age 18-60 years; the condition listed is rabies. Enrollment was 103.

Participants were assigned to groups involving chloroquine, atovaquone and proguanil (Malarone), doxycycline, or rabies vaccine alone. The registry lists rabies vaccine in each of the antimalarial groups as well as in the rabies group. It describes an FDA-approved post-exposure vaccine regimen without rabies immune globulin. The record identifies the antimalarial regimens as FDA-approved malaria chemoprophylaxis regimens, but does not give a detailed rationale for selecting these particular groups.

The schedules differed between the antimalarial groups and the rabies group. Participants in the chloroquine, Malarone, and doxycycline groups received antimalarial treatment up to day 14 and vaccine doses on day 14, day 17, day 21, and day 28. The rabies group received vaccine doses on day 0, day 3, day 7, and day 14. The primary endpoint was measured 14 days after the fourth dose, so its stated timeframe was 6 weeks for the antimalarial groups and 4 weeks for the rabies group.

Randomization can support a fair comparison of assigned groups, while open-label conduct means the assigned treatments were not masked. The registry record does not report the allocation procedure, whether allocation was concealed, or a detailed protocol for implementing or monitoring the assigned regimens.

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: Group 1: 1 subject was excluded from analysis due to presence of rabies antibody titer at baseline, 1 was excluded due to use of steroids during the study; Group 2: 1 subject completed primary endpoint but did not complete the study; Group 3: 1 subject was excluded from analysis due to presence of rabies antibody titer at baseline

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.

Population: Group 1: 1 subject excluded from analysis due to presence of rabies antibody titer at baseline; 1 excluded due to use of steroids during the study. Group 3: 1 subject excluded from analysis due to presence of rabies antibody titer at baseline

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value, measured over 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group.

The primary endpoint was the geometric mean titer (GMT) of rabies virus-specific serum antibodies 14 days after the fourth dose of post-exposure prophylaxis. Titers were measured with a rabies virus antibody neutralization assay using the rapid fluorescent foci inhibition test (RFFIT). The unit was IU/ml. The registry states that a titer greater than 0.5 IU/ml against rabies virus was considered protective.

A GMT summarizes antibody titers on a multiplicative scale. In general, this can be useful when measurements are positive and their variation is better represented proportionally than by an additive scale. A GMT is a group summary; it does not show each participant’s titer or the proportion of participants above a threshold. The protective threshold therefore should not be interpreted as a classification of everyone in a group based on the group GMT.

The endpoint was intended to describe antibody response after the fourth vaccine dose and inform the stated question about whether a fifth dose would add value. The registry reports group GMTs and geometric coefficients of variation. It does not report confidence intervals, individual-level results, or the proportion of participants with titers above the protective threshold. Consequently, the posted summaries do not establish the precision of the GMT estimates or how many individuals met that threshold.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a geometric mean titer represent?

The endpoint is a geometric mean titer, rather than an arithmetic average. In general, a geometric mean is calculated on a logarithmic scale and then expressed back on the original measurement scale. This approach is often used for antibody titers because changes that are proportional can be more meaningful than changes by a fixed additive amount. The reported GMT gives a summary of a group’s measured titers; it does not describe the distribution of every participant’s result.

The registry also reports a geometric coefficient of variation for each group. In general, a coefficient of variation expresses spread relative to the scale of the mean, and a geometric version is suited to multiplicative data. It is a measure of variability among observations, not a measure of how precisely the GMT has been estimated. Confidence intervals or standard errors would be needed to describe uncertainty in an estimate, and these are not reported in the registry record.

Why does the assay and threshold matter?

The antibody outcome was measured by RFFIT, a rabies virus-specific serum antibody neutralization assay. The record defines a titer greater than 0.5 IU/ml as protective. That threshold applies to a titer measurement, not directly to a group GMT. A group mean above a threshold would not show that every participant was above it, nor would it reveal the share above it. The registry does not report participant-level threshold results or the proportion meeting the threshold.

What can randomization contribute?

In general, random assignment is used to make treatment groups comparable in expectation, reducing the risk that group differences are caused by participants choosing their own treatment. It does not guarantee that groups will be identical, particularly in a trial with limited enrollment. Randomization also does not remove uncertainty from estimates or resolve missing outcome data. The record says that the trial was randomized, but the allocation method and concealment procedures are not reported in the registry record.

The trial was open label, meaning the assigned regimens were not masked. In general, lack of masking can affect behavior, reporting, or other aspects of study conduct, depending on the outcome and its measurement. The primary endpoint was an assay-based antibody measure, but the registry record does not report whether laboratory staff were masked to group assignment. It is therefore not possible to assess that aspect of outcome measurement from the record.

How should group comparisons be assessed?

A difference between two reported group means is an estimate, not by itself evidence that the underlying groups differ. General statistical interpretation considers both the size of an estimated effect and its uncertainty. A confidence interval can show a range of values compatible with the data under the model; a hypothesis test can assess compatibility with a specified null hypothesis. Neither a confidence interval nor a primary endpoint test is reported in the registry record. No such estimate or test should be inferred from the GMTs alone.

The record lists a control group and three antimalarial groups, but the posted primary results are descriptive. There are multiple possible comparisons, and the registry does not report which formal comparison, if any, was designated for inference beyond the endpoint description. A statistical plan, including model choice, covariate adjustment, handling of repeated measurements, and any multiplicity procedure, is not reported in the registry record.

What does over-dispersion mean in general?

Over-dispersion is a general term for observed variability greater than expected under a statistical model. It is important when a model assumes a particular amount of variation: if the assumption understates actual variability, standard errors can be too small and confidence intervals too narrow. The endpoint record reports geometric coefficients of variation, but does not identify a model or state that over-dispersion was evaluated. No claim about over-dispersion in this trial can be made from the posted summaries.

How should planning illustrations be read?

In general, a sample-size calculation describes the participants per arm that a hypothetical study might require under specified assumptions. It is a planning illustration, not evidence that the current trial had a particular probability of detecting an effect. The registry record describes planning illustrations based on an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect set as a stated fraction of the observed effect. These assumptions do not establish that they were used to design this trial. No sample-size justification or design calculation is reported in the registry record, and a planning illustration should not be described as observed power.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists three secondary outcomes in addition to the primary endpoint. They concern GMT before the third dose, before the fourth dose, and 28 days after the fourth dose. Considering multiple outcomes or multiple group comparisons raises a general statistical issue: the more inferential tests performed, the greater the chance of a false-positive result unless the analysis plan accounts for multiplicity. The registry record does not report a multiplicity adjustment, a hierarchy of tests, or a prespecified strategy for interpreting the secondary outcomes. It also lists no posted statistical analyses.

The primary endpoint description notes some exclusions and incomplete study participation. It states that one participant in Group 1 was excluded for a baseline rabies antibody titer and one for steroid use during the study; it also notes that one participant in Group 2 completed the primary endpoint but did not complete the study. The description for Group 3 is truncated, so its full account is not reported in the registry record. The endpoint summaries list analyzed group sizes, but a complete participant flow and a full account of missing measurements are not reported.

In general, missing data can affect results if the participants with available measurements differ systematically from those without them. The registry record does not report the assumptions or methods used to handle missing outcomes, whether any sensitivity analyses were done, or the complete analysis population definition. It is therefore not possible to assess how missing data or exclusions may have affected the reported GMTs.

11. 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 as zero in each listed group and deaths as zero in each listed group. The numbers at risk for serious adverse events were 25 for chloroquine, 26 for Malarone, 27 for doxycycline, and 25 for rabies vaccine alone. These are the reported group figures; they should not be converted into rates without an appropriate analysis and denominator definition.

The record also reports other adverse events affecting 17 participants in the chloroquine group, 22 in the Malarone group, 19 in the doxycycline group, and 19 in the rabies group. These are counts, not measures of severity or causal attribution. The registry excerpt does not provide event descriptions or clarify how many events each affected participant experienced. No serious adverse event terms are listed.

Zero reported serious events does not establish that a regimen has no risk. In general, safety estimates depend on the number of people observed, the duration and completeness of follow-up, event definitions, and how events were collected. These details are not fully reported in the registry record, so the safety figures should be read as descriptive counts rather than as a complete assessment of safety.

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

The registry results describe antibody GMTs after a fourth dose of rabies vaccine among participants assigned to chloroquine, Malarone, doxycycline, or rabies vaccine alone. The reported endpoint values differ numerically, and the accompanying geometric coefficients of variation describe group-level variability. The record does not report inferential comparisons or confidence intervals, so it does not establish whether the observed differences are compatible with chance variation or represent a statistically supported effect.

The endpoint was chosen to address the antibody response after dose four and the stated question of whether an additional dose would add value. The reported results do not directly evaluate a fifth dose: no outcome after a fifth dose is listed. Nor do the group GMTs establish the proportion of participants whose titers exceeded the registry’s protective threshold. The antibody endpoint is not the same as measuring rabies illness or protection following an actual exposure.

The record supports a description of the trial structure, vaccine schedules, measured antibody outcome, and posted group summaries. It does not support a conclusion that an antimalarial caused a particular change in antibody response, that the regimens are equivalent, or that any group had better clinical outcomes. Those conclusions would require analyses and outcomes that are not reported in the registry record.

In general, a result’s interpretation depends on both its estimate and its uncertainty, along with the design and completeness of the data. Here, the registry record does not report a statistical analysis plan, primary endpoint test, interval estimates, or a complete account of missing data. The findings should therefore be treated as descriptive and exploratory, consistent with the trial’s stated exploratory purpose.

13. Why This Trial Matters Statistically

This trial raises a useful statistical question about interpreting immunogenicity outcomes: a group-level antibody summary is not the same as the proportion of individuals meeting a threshold. The primary outcome is a geometric mean titer, while the registry separately defines a protective titer threshold. Without individual threshold classifications, the GMT alone cannot answer how many participants crossed that threshold.

The schedules make timing important to interpretation. Each group’s primary endpoint was measured 14 days after its fourth vaccine dose, but the antimalarial groups and the rabies group reached that point at different elapsed times from their first dose. The reported endpoint is therefore tied to dose number and time since dose four, not to a common time since the beginning of vaccination.

The record also illustrates why descriptive results and inferential results should be distinguished. Group means can be compared numerically, but a statistical conclusion requires information about uncertainty and a defined analysis. The registry reports GMTs and measures of spread, but no confidence intervals or primary comparison analysis. That distinction is especially relevant when several intervention groups and secondary outcomes are listed.

Finally, the record’s incomplete account of exclusions and missing data limits assessment of how the analyzed participants relate to everyone enrolled. These issues do not erase the descriptive information, but they define what it can support. Clear reporting of analysis populations, missingness, and planned comparisons is important for judging whether an observed immunogenicity pattern is robust.

14. 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 a statistical analysis plan, a formal analysis of the primary endpoint, confidence intervals, or p-values. The posted group summaries therefore do not quantify uncertainty around the GMTs or establish whether groups differ statistically. No adjusted estimate is reported.

The primary endpoint population description is incomplete. It mentions exclusions for baseline antibody titer and steroid use, and incomplete study participation, but the full description for Group 3 is truncated. A complete participant flow, analysis population definition, and account of missing endpoint measurements are not reported in the registry record.

The endpoint is an antibody measure rather than a clinical outcome. The registry defines a protective titer threshold but does not report the proportion of individuals above it. The group GMTs cannot substitute for those individual-level results. The record also does not report outcomes after a fifth vaccine dose, despite the stated question about whether a fifth dose would add value.

The vaccine schedules differed between antimalarial groups and the rabies group, and their endpoint timeframes were 6 weeks and 4 weeks, respectively. The registry record does not describe a method to account for this difference in elapsed time. The record also does not report whether laboratory staff were masked, the allocation procedure, or full details of adverse-event collection and follow-up. These gaps limit interpretation of both the efficacy-related antibody summaries and the safety counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Antimalarial Drugs to Rabies Vaccine for Post-exposure Prophylaxis. — NCT02564471.
• Registry record last updated 2021-05-13; status last verified 2021-04.
• Results first posted 2021-04-13.
• 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.

18. Record Summary

NCT02564471 is a completed, randomized, open-label, parallel-group Phase 4 trial sponsored by State University of New York - Upstate Medical University. It enrolled 103 and was described as an exploratory study in healthy US adults age 18-60 years. The groups involved chloroquine, atovaquone and proguanil (Malarone), doxycycline, or rabies vaccine alone.

The primary outcome was GMT of rabies virus-specific serum antibody 14 days after the fourth vaccine dose, measured by RFFIT. The registry reports group GMTs and geometric coefficients of variation, but no posted statistical analyses, confidence intervals, or formal comparison results. It lists three secondary GMT outcomes. The record also reports zero serious adverse events and zero deaths in each group, alongside counts of other adverse events. Important details about the complete analysis population, missing data, and statistical methods are not reported in the registry record.