Adefovir Plus Vaccination in Transplant Patients Without Hepatitis B That Receive a Core Antibody Positive Liver: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Adefovir Plus Vaccination in Transplant Patients Without Hepatitis B That Receive a Core Antibody Positive Liver (NCT01146808), a na phase 1, phase 2 study. The primary outcome is Development of de Novo Hepatitis B Infection After Transplant With a Core Antibody Positive Liver.

2. Clinical Question

The registry lists prevention of de novo hepatitis B as the primary purpose. It also describes a second objective: evaluating whether accelerated vaccination induces hepatitis B surface antibody responses that could obviate life-long antiviral therapy. That objective is distinct from the primary infection endpoint. The secondary outcomes include sustained hepatitis B surface antibody titer >500 IU/mL prior to and after vaccination, and de novo infection assessed at 6 months after adefovir withdrawal. The registry record does not report results for these outcomes.

3. Trial Design

This is a completed Phase 1 and Phase 2 study with a single-group model. The registry lists enrollment of 16 and adefovir dipivoxil plus hepatitis B vaccination as the intervention. Allocation is recorded as NA, and masking is recorded as none. There is no randomized or concurrent control group described, so the design is not a like-for-like treatment comparison.

The study population is described as recipients who are HBsAg seronegative before transplant and receive grafts from hepatitis B core antibody positive donors. The intervention description specifies adefovir 10mg orally each day, with adjustment for renal function, and an option for double-dose hepatitis B vaccination. The record does not describe the decision process for vaccination, the timing of vaccination, or how long each participant received adefovir.

The registry records the study as completed. Its listed start is 2006-03, and primary completion is 2011-09. The primary outcome timeframe is standard-of-care visits post-transplant for 2 years. These dates and the stated timeframe describe the record, but do not establish how many participants completed follow-up or had evaluable endpoint data.

The record lists 3 outcome measures and 0 analyses. It does not report a protocol-level statistical analysis plan, planned sample-size justification, interim analyses, or details of analysis populations. The planning assumptions associated with sample-size illustrations are described as a two-arm, equal-allocation calculation using a two-sided significance level of 0.05 and a normal approximation. That hypothetical setup differs from the registry’s single-group design, and the illustrations are not the trial’s design or observed power.

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

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 Development of de Novo Hepatitis B Infection After Transplant With a Core Antibody Positive Liver, measured over Standard of care visits post-transplant for 2 years.

The primary endpoint counts participants who develop de novo hepatitis B infection after transplant with a hepatitis B core antibody positive liver. The registry defines infection using positive HBsAg serology and an HBV DNA viral load >40 IU/mL. The stated assessment period is standard-of-care visits post-transplant for 2 years.

This is a binary outcome at the participant level: a participant either meets the stated infection definition during the specified period or does not. Reporting a count can describe how many participants had the event, but interpretation also depends on the number with available endpoint assessment and the completeness of follow-up. The registry record does not report the primary endpoint count, the number assessed, or an analysis estimate.

The endpoint is relevant to the stated prevention objective because it operationalizes the infection the study sought to monitor after transplantation. Requiring both positive HBsAg serology and an HBV DNA value above the stated threshold makes the registry’s case definition explicit. It does not, by itself, indicate the timing of infection, the pattern of tests used, or how discordant or missing test results were handled; these details are not reported in the registry record.

The endpoint should be distinguished from the antibody-response outcomes. A surface antibody titer is an immune-response measure, whereas the primary outcome is the development of infection as defined by serology and viral load. The record does not provide results for either type of outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is recorded as a count of participants with an event. For a binary outcome, a participant is classified according to whether the specified event occurred during the defined assessment period. A count is a direct description of events, but it is not fully interpretable without knowing how many participants were assessed and how missing or incomplete follow-up was handled. The registry record does not report those details for the primary endpoint.

What does the endpoint definition require?

The registry defines de novo infection by positive HBsAg serology and HBV DNA viral load >40 IU/mL. In general, a case definition sets a consistent rule for deciding which observations qualify as events. Requiring both specified findings distinguishes the endpoint from an antibody response alone. The record does not state how testing intervals were selected, how borderline or discordant results were adjudicated, or whether endpoint status was reviewed by an independent committee.

What can a single-group count estimate?

In a single-group study, the observed event count can describe outcomes among participants who received the intervention and had outcome assessment. If the relevant denominator is known, an event proportion can also describe the observed frequency in that group. No primary event count or evaluable denominator is reported, so neither an event proportion nor an estimate of precision can be stated. A single-group description also does not provide a treatment contrast. General causal interpretation requires a credible comparison that addresses what would have happened under an alternative treatment or in its absence.

How should precision be considered?

A confidence interval expresses uncertainty around an estimate under a statistical model. It helps readers distinguish a relatively precise estimate from one that remains compatible with a broad range of values. It does not correct for bias, incomplete follow-up, or an unsuitable endpoint definition. The registry record does not report a primary endpoint estimate or confidence interval, so its precision is not assessable. With binary outcomes, the amount of information depends on both the number assessed and the number of events; neither can be replaced by the enrollment figure alone.

What do the planning assumptions mean?

The planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is also described as targeting a stated fraction of an observed effect. Those are assumptions for a hypothetical planning calculation, not evidence that the trial was designed or analyzed that way. The registry design is single group, so equal allocation between two arms does not match the listed trial structure. The illustrations are not observed power, and they do not supply a missing primary outcome result. The trial’s own sample-size justification and statistical plan are not reported in the registry record.

What does the absence of analyses imply?

The registry lists 0 analyses. This means the record does not present an analysis entry for the listed outcomes. It does not establish that no analysis was conducted outside the registry, nor does it reveal the direction or magnitude of any unposted finding. There is no reported adjustment method, model, hypothesis test, or handling of repeated measurements. For a count-based binary endpoint, analyses might in general report an event count and a proportion with uncertainty, but no such primary outcome analysis is reported in this record.

Why can safety counts not answer the primary question?

Safety outcomes and infection outcomes are different measures, even when both are counts of participants. The adverse-event figures describe serious and other adverse-event categories and deaths. The primary outcome instead uses a specified hepatitis B infection definition. A zero in an adverse-event category does not imply a zero for the infection endpoint. Each outcome requires its own definition, denominator, follow-up, and result.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("ADV Plus Hepatitis B Vaccination Group")
n      <- c(16)
events <- c(5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  ADV Plus Hepatitis B Vaccination Group  16  5  31.2  11.0  58.7  14.2  55.6  14.2  56.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures: the primary infection outcome and secondary outcomes concerning hepatitis B surface antibody titers and infection after adefovir withdrawal. Testing or interpreting several outcomes can raise multiplicity concerns because examining multiple findings may increase the chance of highlighting a result that appears unusual by chance. In general, a statistical plan may specify a primary outcome, order secondary questions, or adjust inference across multiple tests. Such a plan is not reported in the registry record.

The record lists 0 analyses, so it does not provide tests, estimates, confidence intervals, or a stated approach to multiplicity. The registry’s designation of a primary outcome identifies its stated priority, but does not reveal how the outcomes were analyzed or whether any adjustment was planned. The listed outcome descriptions alone are not results.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not state how many participants had endpoint tests, how missing visits or incomplete testing were handled, or whether all enrolled participants were included in outcome analyses. Enrollment of 16 should not be taken as proof that all participants had complete follow-up or contributed to every outcome. The number assessed for antibody response or after adefovir withdrawal is also not reported.

These omissions matter because the interpretation of a binary event count depends on follow-up and outcome ascertainment. If participants without complete testing are excluded or treated differently, the reported result could depend on that choice. No such choice can be inferred from this record. The registry status of completed does not itself establish complete outcome reporting.

12. 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.

The adverse-event record lists an ADV Plus Hepatitis B Vaccination Group with 16 at risk and 0 affected for serious events, 16 at risk and 0 affected for other events, and 0 deaths. These are safety-category figures, not the primary de novo hepatitis B outcome. The two at-risk entries refer to separate adverse-event categories and should not be added together.

A reported count of 0 affected means that the registry lists no affected participants for that category in the posted figures. It does not establish that no symptoms, laboratory changes, or events of any kind occurred; the record does not define the full scope of collection in the information available. It also does not show the duration of safety observation or whether every participant contributed the same amount of follow-up.

With no comparator group, the safety figures cannot support a comparative estimate of harms. The record does not report event-specific details, severity grading beyond the serious-event grouping, relatedness assessments, or confidence intervals. The figures should therefore be read narrowly as the posted counts for the named categories, rather than as a complete characterization of safety or as evidence about efficacy.

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

This record establishes that a single-group study evaluated adefovir dipivoxil with hepatitis B vaccination in transplant recipients described as HBsAg seronegative before receiving a liver graft from a hepatitis B core antibody positive donor. It specifies de novo hepatitis B infection as the primary outcome and gives a case definition and follow-up timeframe. It also identifies antibody response and infection after adefovir withdrawal as secondary questions.

The record does not report the primary endpoint result, secondary outcome results, or outcome analyses. It therefore does not show how many participants developed infection, how antibody titers changed, or how many developed infection after antiviral withdrawal. The absence of those results should not be interpreted as a finding of no events or as evidence of benefit or lack of benefit.

Even if event results were available, the single-group design would describe outcomes in the treated group rather than provide a randomized comparison. Without a comparator, the observed course could not be attributed to the intervention alone. This is a general design limitation; it does not determine what the unreported results would be.

The registry does report adverse-event counts, including 0 affected in the serious and other event categories and 0 deaths. Those safety counts are not the primary infection outcome and do not fill the gap in efficacy reporting. They also do not establish a comparative safety profile.

Accordingly, the record supports a description of the research question, intervention, design, outcome definitions, and posted safety counts. It does not support a numerical estimate of infection risk, an estimate of treatment effect, or a conclusion about the immune response. Readers should distinguish the stated objectives from reported findings and the reported safety figures from the unreported primary endpoint.

14. Why This Trial Matters Statistically

This study raises a statistical question in a setting where the outcome definition and follow-up window are central to interpretation. The primary endpoint requires both positive HBsAg serology and HBV DNA above the stated threshold, and the record places assessment during standard-of-care visits post-transplant for 2 years. Clear definitions help readers understand what counts as an event, but useful interpretation also requires the event count, the number assessed, and information about follow-up completeness. Those outcome details are not reported in the registry record.

The single-group design is also statistically important. It can describe what happened among participants receiving the regimen, but it does not directly estimate how outcomes would differ under another strategy. A comparator is essential for a direct between-group contrast; without one, treatment effects are difficult to distinguish from other influences. The record’s planning assumptions describe equal allocation between two arms, while the listed trial model is single group. That contrast illustrates why planning calculations should not be mistaken for the actual design.

The study also separates infection prevention from immune-response questions. A hepatitis B surface antibody titer and a clinically defined infection endpoint measure different things. Their roles should not be conflated, and separate results are needed to assess each objective. The registry lists these outcomes but does not report their analyses.

Finally, the record demonstrates why enrollment and completion status are not substitutes for endpoint reporting. Enrollment is listed as 16 and status as completed, but the number assessed for each outcome and the primary result are not reported. Without those details, statistical precision and the implications of missing follow-up cannot be evaluated. The central statistical lesson is that a precise question and defined endpoint do not, by themselves, provide evidence about the observed result.

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 main trial-specific limitation in interpreting the registry record is the absence of primary and secondary outcome results. The record identifies the outcomes and their definitions but does not report event counts, antibody-response findings, estimates, or uncertainty measures. It is therefore not possible to assess the magnitude or precision of the outcomes from the posted information.

The single-group model and absence of a comparator limit comparative interpretation. The record cannot show how outcomes would differ under another treatment approach. The absence of masking is recorded, but the registry does not explain outcome adjudication or any safeguards against ascertainment bias. In general, objective laboratory criteria may constrain outcome classification, yet the record does not describe laboratory procedures, testing schedules, or adjudication processes.

The record does not report the number of participants with complete follow-up, outcome-specific denominators, or missing-data methods. It also does not say how many participants received vaccination, how vaccination decisions were made, or the duration of adefovir treatment. These details are relevant to understanding which intervention exposure the results would represent, but they cannot be inferred from the arm description.

Additional limitations include the absence of a reported statistical analysis plan, sample-size justification, analysis populations, and multiplicity approach. The planning assumptions describe a two-arm calculation, unlike the single-group trial model, and should not be read as the trial’s actual design or as observed power. The posted adverse-event figures are limited to counts in specified categories and do not replace the missing infection outcome data. These limitations describe what the registry record does not report; they do not establish that the study did not collect or analyze information outside the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Adefovir Plus Vaccination in Transplant Patients Without Hepatitis B That Receive a Core Antibody Positive Liver — NCT01146808.
• Registry record last updated 2021-08-10; status last verified 2021-08.
• Results first posted 2017-03-15.
• 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

The registry record describes a completed Phase 1 and Phase 2, single-group study sponsored by Columbia University. Enrollment is listed as 16, with adefovir dipivoxil plus hepatitis B vaccination as the intervention. The study concerns recipients who are HBsAg seronegative before transplant and receive liver grafts from hepatitis B core antibody positive donors.

The primary outcome is the count of participants developing de novo hepatitis B infection, defined by positive HBsAg serology and HBV DNA viral load >40 IU/mL during standard-of-care visits post-transplant for 2 years. Secondary outcomes concern sustained surface antibody titer >500 IU/mL and infection assessed at 6 months post withdrawal.

The record lists 3 outcome measures and 0 analyses. It does not report primary or secondary outcome results, outcome-specific denominators, missing-data handling, or a statistical analysis plan. Posted adverse-event figures list 0 affected for serious events, 0 affected for other events, and 0 deaths. These safety figures do not provide the missing primary infection result.