A Safety and Efficacy Study of the Hepatitis E Vaccine in Nepal.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Efficacy Study of the Hepatitis E Vaccine in Nepal. (NCT00287469), a randomized phase 2 study. The primary outcome is Percent of Participants of Definite Hepatitis E by Category and Immunological Markers (Anti HEV) During the Follow-up Period.

2. Clinical Question

The registry states that the study aimed to assess whether the candidate vaccine was safe and able to prevent symptomatic liver disease due to hepatitis E virus. The primary outcome description defines definite disease using an illness lasting at least 3 days, at least 3 listed symptoms, and a peak alanine aminotransferase (ALT) value greater than 2.5 times the upper limit of normal. The outcome title also refers to anti-HEV immunological markers. The record does not provide primary outcome values, a treatment-effect estimate, or a comparison between arms for this endpoint. It therefore permits a description of the question and outcome definition, but not a conclusion about the size or precision of any efficacy effect.

3. Trial Design

This was a phase II, prospective, randomized, double-blind, placebo-controlled, parallel-group field efficacy trial in Nepal. The registry lists enrollment as 2000 and status as completed. The recorded study start date is 2001-07-09, and the primary completion date is 2004-01-19. The sponsor is the U.S. Army Medical Research and Development Command.

Participants were assigned to receive either 20mcg of recombinant HEV antigen or placebo. Both were administered intramuscularly in the deltoid according to a 0, 1 and 6 month schedule. The placebo is described as PBS buffer containing alum. The registry identifies the allocation as randomized and masking as double. It does not describe the randomization sequence, concealment procedures, who was masked, or how masking was maintained. Those details are not reported in the registry record.

A parallel-group design compares assigned groups over the course of the trial rather than having participants cross between interventions. Randomization is intended, in general, to make assigned groups comparable at baseline on average. Double masking is intended, in general, to reduce the influence of treatment knowledge on participant experience, clinical assessment, and outcome recording. These design features do not by themselves establish that the groups were comparable in practice or that outcome assessment was free from bias; the registry record does not provide information to evaluate those points.

The primary outcome timeframe is 14 days after dose 3 at 6 months. The registry also lists secondary outcomes concerning the percentage of participants with definite hepatitis E by category during follow-up and the number of suspected, definite, probable, and not confirmed hepatitis E cases. Detailed follow-up procedures, eligibility criteria, analysis populations, and the statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Percent of Participants of Definite Hepatitis E by Category and Immunological Markers (Anti HEV) During the Follow-up Period, measured over 14 days after dose 3 at 6 months.

The primary endpoint is described as the percent of participants with definite hepatitis E by category and anti-HEV immunological markers during the follow-up period. Its specified timeframe is 14 days after dose 3 at 6 months. The registry defines an illness criterion as symptoms lasting at least 3 days and including at least 3 of fatigue, loss of appetite, abdominal discomfort, right upper quadrant pain, nausea, and vomiting. It also specifies a peak ALT greater than 2.5 times the upper limit of normal, expressed in the record as 2.5 x 42 =105.

A percentage expresses how common an outcome was in a defined group, using the number meeting the outcome definition relative to the relevant group denominator. The record gives the formula as n x 100 / N, but does not report the endpoint counts, denominators, or resulting percentages. It also does not explain the categories used in the endpoint title or provide values for the immunological markers.

In general, a symptom-and-laboratory definition can make an endpoint more specific than symptoms alone by requiring both a clinical pattern and a laboratory finding. Its usefulness for comparing assigned groups depends on consistent measurement and complete follow-up. The registry record does not provide enough information to assess how these criteria were applied in practice or whether all participants contributed endpoint data.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies a randomized, double-blind, parallel-group design and a percentage endpoint with a 95% confidence interval as its dispersion measure. It does not report the statistical methods used to analyze the primary endpoint. The concepts below describe how such methods are generally interpreted; they are not claims about analyses performed in this trial.

What does randomization contribute?

In general, randomization assigns participants to interventions by chance. Its purpose is to reduce systematic differences between groups at the point of assignment, including differences in factors that are known and unknown. Randomization does not guarantee identical groups, and it does not correct for missing outcome information, measurement errors, or departures from the assigned treatment. The record does not describe sequence generation, allocation concealment, stratification, or checks of baseline comparability.

How should a percentage endpoint be read?

A percentage is a binary-outcome summary: each participant either meets the specified outcome definition or does not, and the number meeting it is related to the group denominator. The registry gives the formula n x 100 / N. To interpret a percentage, readers need to know what counts as an event, the population included in the denominator, and the period over which events are counted. The clinical definition and timeframe are stated, but outcome counts and denominators for the primary endpoint are not reported in the registry record.

For a between-group comparison, analysts may report group-specific percentages and an effect measure such as a difference in percentages or a ratio. These measures answer different questions and have different scales. No such primary endpoint comparison is reported, so no effect measure can be interpreted.

What does a 95% confidence interval communicate?

In general, a confidence interval describes the uncertainty around an estimate under a specified statistical procedure. It is not a measure of whether the study was well designed, and it does not account for every possible source of bias. Its interpretation depends on the estimate, model, and assumptions used. Although the registry lists a 95% confidence interval for the primary endpoint, it does not give the interval limits or analysis method. Precision therefore cannot be judged from the record.

Why can event counts require careful modeling?

For a binary percentage, the amount of information depends partly on the number of participants with and without the event and on the denominator. General statistical methods can use models or standard formulas to estimate uncertainty, but the suitability of a method depends on the data structure and analysis population. If observations are more variable than a model assumes, standard errors and confidence intervals may be misleading; general approaches can account for such over-dispersion when appropriate. The registry does not report a model, a dispersion assessment, or any evidence that over-dispersion was evaluated. This is a general consideration, not an assertion that over-dispersion occurred in this trial.

How do masking and outcome definition affect analysis?

In general, masking can reduce the chance that knowledge of assigned treatment influences reporting, assessment, or decisions about whether an outcome is present. A written outcome definition can also support consistent classification across groups. The definition in this record combines symptom duration, a symptom count, and an ALT threshold. The record does not describe how symptoms or laboratory values were collected, adjudicated, or handled when information was incomplete. The practical consistency of classification therefore cannot be assessed.

What is missing from the statistical report?

The registry lists zero analyses and does not report a statistical analysis plan, model specification, hypothesis test, p-value, adjusted estimate, or primary endpoint confidence interval. It also does not report whether any interim analyses were planned or conducted, how sample size was justified, or how protocol deviations were handled. A completed trial status does not itself supply these missing analytic details. Without them and without primary endpoint estimates, the registry record cannot support a reconstruction of the efficacy analysis.

Statistical significance and clinical importance are also distinct concepts in general. A p-value, if reported, would describe compatibility of data with a specified statistical model and null hypothesis; it would not quantify the size or importance of an effect. An estimate and its interval are needed to assess magnitude and precision. Neither is available for the primary endpoint in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint with categories and immunological markers, along with secondary outcomes covering definite hepatitis E by category and counts of suspected, definite, probable, and not confirmed cases. It reports three outcome measures and zero analyses. The record notes that the primary outcome has several categories or time points and is not reduced to one comparison. Consequently, there is no single primary comparison in the posted results to interpret.

Multiplicity arises in general when several outcomes, categories, time points, or statistical tests are examined. The more comparisons made, the greater the chance that at least one may appear unusual by chance if each is interpreted in isolation. Statistical plans may address this through a prespecified primary comparison, adjusted testing, or a hierarchy of outcomes. Whether any such approach was used is not reported in the registry record. The endpoint structure alone does not establish that an adjustment was necessary or performed.

The registry does not report endpoint values, analysis populations, missing-data counts, reasons for missingness, or methods for handling missing outcomes. It therefore is not possible to determine how many participants contributed to the primary endpoint, whether all randomized participants were analyzed, or whether the primary analysis followed assignment regardless of treatment received. These details matter because complete-case analyses, imputation, and other approaches can rely on different assumptions.

In general, missing data can affect both the estimate and its uncertainty, particularly if the likelihood of missingness is related to outcome status or assigned group. The record does not describe such patterns or any sensitivity analyses. No inference about the impact of missing data or multiplicity can be made from the registry information.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hepatitis e (8.1%), typhoid fever (3.0%), leptospirosis (1.2%), viral infection (0.9%), gun shot wound (0.9%).

The registry reports serious adverse event counts as 200 of 1000 participants in the placebo group and 143 of 1000 in the 20mcg Recombinant HEV group. For other adverse events, it reports 226 of 1000 in the placebo group and 229 of 1000 in the vaccine group. The recorded death counts are 1 for placebo and 6 for the vaccine group. These figures are descriptive entries, not a statistical comparison.

The record also lists serious adverse event terms and percentages: Hepatitis E, 8.1%; Typhoid fever, 3.0%; Leptospirosis, 1.2%; Viral infection, 0.9%; Gun shot wound, 0.9%; and Paratyphoid fever, 0.8%. The record does not explain the denominator or calculation used for these term percentages. They should therefore be read as listed terms rather than as group-specific rates or evidence of a causal relationship.

In general, safety counts need context about how events were defined, collected, coded, and followed, and whether the same procedures were used in each group. A count alone does not establish causation or indicate whether groups differ beyond what could occur by chance. The registry does not report inferential analyses, event timing, severity grading, or attribution procedures for these summaries. The posted figures should not be read as a complete assessment of safety.

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

The record establishes that a phase II randomized, double-blind, placebo-controlled trial evaluated a candidate hepatitis E vaccine in Nepal. It identifies the vaccine schedule, placebo, primary endpoint definition, follow-up timeframe, and selected safety summaries. Those details help readers understand the intended comparison and what the investigators meant by definite hepatitis E.

The record does not establish the primary endpoint result. No group-specific primary outcome percentages, effect estimate, confidence interval, or analysis are reported. As a result, the posted information cannot quantify whether the groups differed in definite hepatitis E, how large any difference might have been, or how precise an estimate would be. The record's description of a study purpose is not evidence of an observed efficacy result.

The safety counts document reported adverse-event summaries, but do not by themselves show that an intervention caused or prevented an event. The registry does not provide the statistical comparisons and clinical details needed to interpret those counts fully. Likewise, the listed serious adverse event terms and percentages lack a stated denominator in the record.

In general, a trial result is interpreted by considering the estimated effect, its uncertainty, the endpoint definition, the population analyzed, and the conduct of the study. A completed status does not replace these results. Missing information about analyses, missing data, and outcome assessment limits what can be inferred from the registry record. These limits concern interpretation of the posted record; they do not establish what the full study report may contain.

13. Why This Trial Matters Statistically

This trial is statistically notable as a randomized, double-blind comparison using a clinically defined hepatitis E outcome rather than relying only on a broad symptom report. The endpoint combines a minimum duration of illness, a specified symptom pattern, and a laboratory threshold. In general, defining an outcome in advance can make the intended event clearer and improve consistency of interpretation. The registry provides these criteria and the stated assessment timeframe, allowing readers to see what the primary question was intended to measure.

The design also illustrates why a trial's question and its results must be distinguished. Randomization and masking describe methods intended to support a fair comparison, while outcome estimates and uncertainty quantify what the observed data show. The record includes design details but does not report the primary outcome analysis. Readers can therefore assess the intended design at a broad level, but cannot assess the precision or magnitude of an efficacy estimate.

The safety summaries provide another statistical lesson: raw counts need denominators, definitions, and analytic context. Even with group denominators listed for the adverse-event summaries, the registry does not supply formal comparisons or enough detail to infer causation. Percentages attached to serious adverse event terms have no stated denominator in the record.

Finally, the presence of multiple outcome categories and secondary measures makes transparent reporting of analysis choices important. The registry does not describe how multiplicity, missing data, or analysis populations were handled. This trial therefore shows both the value of clear outcome definitions and the limits of a record that lacks outcome estimates and analysis details.

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 most consequential limitation of the registry record for statistical interpretation is the absence of primary outcome results. It gives no outcome counts, group-specific percentages, confidence interval limits, or treatment-effect estimate for definite hepatitis E. Although a 95% confidence interval is named as the dispersion measure, its values and the method used to calculate it are not reported in the registry record.

The endpoint is described as being reported by category and immunological markers, but the categories and marker results are not detailed. The record does not clarify how the clinical definition was applied when symptom information or laboratory measurements were incomplete, nor does it describe the timing and consistency of assessment across groups. The listed timeframe is 14 days after dose 3 at 6 months, but additional follow-up details are not reported.

Important population and analysis information is also absent. Eligibility criteria, baseline characteristics, analysis populations, missing outcome counts, treatment adherence, withdrawals, and protocol deviations are not reported in the registry record. These omissions prevent assessment of the participants included in the endpoint denominators and of possible differences between enrolled and analyzed populations.

The registry identifies randomization and double masking, but does not describe sequence generation, allocation concealment, masking procedures, or outcome adjudication. It does not report the statistical analysis plan, model, multiplicity approach, interim analyses, or sample-size justification. The safety entries likewise lack detailed definitions, event timing, attribution, and inferential comparisons; the basis for the serious-event term percentages is not stated. These limitations apply to interpretation of the registry record and do not establish whether additional information exists elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Safety and Efficacy Study of the Hepatitis E Vaccine in Nepal. — NCT00287469.
• Registry record last updated 2019-05-29; status last verified 2019-05.
• Results first posted 2019-05-29.
• 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

The registry describes a completed phase II, prospective, randomized, double-blind, placebo-controlled, parallel-group field efficacy trial of a candidate hepatitis E vaccine in Nepal. It lists enrollment of 2000, a study start date of 2001-07-09, and a primary completion date of 2004-01-19. The vaccine was 20mcg recombinant HEV antigen, administered intramuscularly in the deltoid on a 0, 1 and 6 month schedule; the placebo was PBS buffer containing alum and followed the same schedule.

The primary endpoint concerned the percentage of participants with definite hepatitis E by category and anti-HEV markers, assessed 14 days after dose 3 at 6 months. The definition included specified symptoms and an ALT threshold. The registry reports safety counts and serious adverse event terms, but no primary endpoint results or analyses. Statistical plan details, missing-data handling, and analysis populations are not reported in the registry record.