Suboptimal Responders to Adefovir Switching to Entecavir: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Suboptimal Responders to Adefovir Switching to Entecavir (NCT00718887), a randomized phase 4 study. The primary outcome is Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing.

2. Clinical Question

3. Trial Design

The record identifies this as a randomized, unmasked Phase 4 study with a crossover model. Its title describes a comparison of switching to entecavir versus continuing adefovir in adults with chronic hepatitis B and a suboptimal response to adefovir. The study status is completed. Enrollment is recorded as 228.

The intervention listings name entecavir and Adefovir/Entecavir. In the primary outcome results, the two arms are labeled Entecavir, 0.5 mg QD and Adefovir, 10 mg QD. The Week 48 secondary outcome instead labels the comparison arm Adefovir, 10 mg QD/Entecavir, 0.5 mg QD. This is consistent with a record that includes treatment switching, but the schedule, treatment periods, and relationship between the Week 12 and Week 48 assessments are not reported in the registry record.

The primary outcome population is described as participants who were randomized and received at least one dose of study drug. The posted Week 12 arm results list 89 participants for entecavir and 77 for adefovir. The reason the outcome counts differ from the recorded enrollment, and the handling of participants not represented in these arm counts, are not reported in the registry record.

Masking is listed as none. The registry record does not report the allocation ratio, the crossover sequence, washout procedures, treatment adherence, or the protocol’s planned statistical analysis. These details matter when interpreting an outcome from a crossover design, because the timing of treatment and measurement can affect what a between-arm comparison represents.

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: A total of 228 participants were enrolled, of which 169 were randomized. A total of 166 participants received treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who were randomized and received at least 1 dose of study drug.

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 Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing, measured over At Week 12 from Day 1.

The primary endpoint is the percentage of participants with HBV DNA below 50 IU/mL at Week 12, measured by polymerase chain reaction testing. The registry notes that this threshold is approximately 300 copies/mL. HBV DNA is a measure of viral genetic material in the blood; a threshold endpoint records whether each participant’s measured level is below the specified cutoff at the stated assessment.

A percentage makes the outcome interpretable as the proportion of the assessed group meeting that threshold. It does not show the full distribution of HBV DNA values, how far an individual value lies from the cutoff, or how a participant’s result changed over time. Dichotomizing a continuous measurement can also make participants with values close to either side of the threshold appear categorically different, even when their measurements are similar.

The endpoint is assessed at Week 12 from Day 1. The registry specifies a primary outcome population of randomized participants who received at least one dose of study drug. It does not report how missing Week 12 measurements were handled, whether the threshold was selected in advance in the protocol, or the laboratory and analysis details beyond polymerase chain reaction testing.

7. Results Posted in the Registry

• Adefovir, 10 mg QD: 0.0% (0/77) versus 5.6% (5/89) on control; risk difference -5.6 percentage points (95% CI -10.4 to -0.8); unadjusted two-proportion z-test p = 0.035.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Adefovir, 10 mg QD/Entecavir, 0.5 mg QD: 28.6% (22/77) versus 31.5% (28/89) on control; risk difference -2.9 percentage points (95% CI -16.8 to 11.1), risk ratio 0.91 (0.57–1.45); unadjusted two-proportion z-test p = 0.686.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Adefovir, 10 mg QD/Entecavir, 0.5 mg QD and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the questions beyond the primary Week 12 threshold. They include a Week 48 HBV DNA threshold, mean log10 reduction in HBV DNA, ALT normalization, HBeAg loss and seroconversion, HBsAg loss and seroconversion, genotypic resistance to entecavir, adverse events and laboratory abnormalities. The registry lists these outcome topics, but results are not reported for most of them in the posted record.

The available Week 48 HBV DNA result reports 31.5% for entecavir and 28.6% for the arm described as Adefovir, 10 mg QD/Entecavir, 0.5 mg QD. Its unadjusted p-value is 0.686, and the confidence interval for the risk difference includes zero. This later comparison has a different comparator description from the primary Week 12 result, so the two assessments should not be treated as directly interchangeable or as a simple account of persistence over time.

The primary Week 12 result and the available Week 48 result address the same threshold outcome at different times, but their reported contrasts differ in arm description and precision. The registry does not provide enough detail about treatment sequence, crossover timing, or analysis to explain the relationship between them. The other listed secondary outcomes cannot be used to confirm or contradict the primary result because their outcome results are not reported in the registry record.

General explanation: secondary outcomes can help describe consistency across different measures, but multiple testing makes isolated unadjusted findings harder to interpret. When many outcomes are assessed, the chance of observing a seemingly notable result by chance can increase. The registry does not report a multiplicity adjustment or a hierarchy governing secondary outcomes. Accordingly, the unadjusted secondary results warrant less weight than a result supported by a prespecified, fully reported analysis plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing
• Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing
• Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT)
• Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion
• Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion
• Number of Participants With Genotypic Resistance to Entecavir
• Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation
• Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results

9. Statistical Interpretation

10. Statistical Methods Explained

What does the percentage measure?

For a binary endpoint, each participant is classified according to whether the event occurred or the specified condition was met. The percentage is the proportion meeting that condition among the participants included in the calculation. In this trial, the condition is having HBV DNA below 50 IU/mL at Week 12. The registry reports the percentages and the arm counts of participants meeting the threshold; it does not provide the individual measurements.

General explanation: a binary endpoint is easy to describe, but it discards information about the magnitude of measurements. Two participants on opposite sides of a cutoff may have very similar measured values, while participants on the same side may have quite different values. The percentage therefore answers a threshold question rather than describing the complete change in HBV DNA.

What does the risk difference represent?

The risk difference compares the outcome proportions between two groups by subtracting one proportion from the other. Its sign depends on which group is treated as the reference. For the Week 12 comparison, the registry identifies entecavir as the control group and adefovir as the comparison arm. The reported estimate is therefore oriented as adefovir relative to entecavir. Its negative direction matches the lower observed percentage in the adefovir arm.

General explanation: a risk difference is an absolute contrast in proportions, not a relative percentage change. It can be interpreted in the units of the outcome percentages, but the registry’s reported estimate is on a proportion scale. The arm percentages are the clearest direct description of the observed results.

What does the p-value say?

The Week 12 unadjusted p-value is 0.035. General explanation: a p-value describes how compatible data are with a specified statistical null model, under the assumptions used for the test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. Because the value is unadjusted, it does not reflect any correction for examining multiple outcomes unless such a procedure was applied separately; one is not reported in the registry record.

The Week 48 unadjusted p-value is 0.686. It accompanies a risk-difference interval that spans zero. This indicates that the posted Week 48 contrast is not estimated precisely enough to rule out no difference under the interval method used. The statistical method for either test is not reported in the registry record, so the exact assumptions behind the p-values and intervals cannot be verified from the record.

Why does the crossover design matter?

General explanation: in a crossover study, participants may receive more than one treatment in a sequence, and outcomes can depend on treatment period, sequence, and any lasting effects from an earlier treatment. A valid analysis may need to account for these features. The registry labels this study as crossover, but does not report the sequences, period-specific results, washout, or analysis model. The posted arm-level comparison should therefore be read in the context of what the registry reports, without assuming how the crossover was handled analytically.

What are planning illustrations?

The Week 48 results include planning illustrations based on fractions of the observed effect. General explanation: such values describe hypothetical sample sizes under the stated planning assumptions; they are not the number of participants enrolled in this trial, and they do not show the trial’s observed power. The registry states assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is defined as a fraction of the observed effect. These planning illustrations do not establish that those assumptions were used to design this trial; the registry explicitly describes them as an illustration rather than the trial’s own design.

11. Confidence Intervals and Precision

A confidence interval gives a range of effect estimates compatible with the observed data under a statistical method and its assumptions. It conveys uncertainty about the estimated contrast; it is not a range containing a stated proportion of individual participant outcomes. General explanation: narrower intervals indicate greater precision, while wider intervals indicate greater uncertainty. Precision depends on the amount and variability of information and on the analysis method.

For the primary Week 12 comparison, the registry reports a risk-difference interval whose bounds are both below zero. This is consistent with the observed direction of the comparison, in which the entecavir arm has a higher reported percentage than the adefovir arm. The interval does not remove uncertainty about the size of the difference, and it does not resolve limitations in the description of the crossover design or the analysis population.

For the Week 48 secondary comparison, the risk-difference interval extends across zero. That interval is compatible with values on either side of no difference under the reported comparison. The Week 48 percentages are close to one another, but the interval indicates that the estimate is not sufficiently precise to distinguish the direction of the underlying contrast with confidence.

The registry provides interval estimates for the reported risk differences, but does not name the interval method or describe its assumptions. It also does not provide confidence intervals for all secondary outcomes in the listed record. The absence of an interval for an outcome should not be mistaken for certainty; it means that the registry does not report that measure of precision.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists secondary outcomes in addition to the primary Week 12 endpoint. It does not report a multiplicity adjustment, a testing hierarchy, or a statistical analysis plan specifying how multiple endpoints would be interpreted. The Week 12 and Week 48 p-values are explicitly unadjusted in the posted comparison information. They should therefore be read as individual, unadjusted tests, not as results corrected for the full set of outcomes.

The registry’s description of the primary outcome population is randomized participants who received at least one dose of study drug. It does not state how participants with missing Week 12 measurements were handled, whether an imputation method was used, or whether there were protocol deviations affecting inclusion. The posted arm counts for the primary result are 89 and 77; the reasons that participants are not represented in those outcome counts are not reported in the registry record.

The record does not report a separate analysis population for the Week 48 endpoint or the other secondary outcomes. It also does not state whether an intention-to-treat analysis was performed, whether participants were analyzed according to randomized assignment, or how crossover periods were incorporated. Those omissions limit assessment of possible selection and missing-data effects.

General explanation: missing outcomes can affect an estimated percentage when the likelihood of a missing measurement is related to treatment or outcome status. The direction and extent of any such effect cannot be determined without information about missingness and the analysis approach. Likewise, an unadjusted p-value does not account for the number of questions tested. These are reporting uncertainties, not evidence that the posted result is necessarily biased.

13. 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: drug hepatitis (1.1%).

The registry reports serious adverse events for 1 of 89 participants in the Entecavir, 0.5 mg QD group and 0 of 77 participants in the Adefovir, 10 mg QD/Entecavir, 0.5 mg QD group. It identifies drug hepatitis at 1.1% as a serious adverse event term. Other adverse events are recorded for 8 of 89 and 9 of 77 participants, respectively.

These counts describe what the registry reports; they do not establish that the treatments have equivalent or different safety profiles. The record does not provide event timing, duration, severity detail beyond the serious-event category, exposure-adjusted rates, or a fuller account of how events were attributed to treatment. The deaths field has no reported count, so the record does not support an inference about deaths. Serious adverse event counts are also small, making direct comparison imprecise. General explanation: safety counts require context about exposure time, definitions, follow-up, and whether participants could receive more than one treatment in a crossover design.

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

The posted primary result shows that the recorded Week 12 percentage below the HBV DNA threshold was higher in the entecavir arm than in the adefovir arm. The reported comparison has an unadjusted p-value of 0.035, and its risk-difference confidence interval lies below zero in the direction defined by the registry. These statistics describe the observed endpoint contrast and its uncertainty under the analysis represented in the registry.

They do not, by themselves, establish the clinical importance of the difference, explain how the crossover design was handled, or show how every randomized participant contributed to the analysis. The registry does not report the full statistical plan, missing-data approach, or detailed treatment sequence. The primary outcome is a threshold measure at one time point, not a complete account of viral response, durability, safety, or other clinical outcomes.

The Week 48 result is a secondary comparison with a different treatment description for the comparator arm. It reports percentages that are relatively close, an unadjusted p-value of 0.686, and an interval that includes zero. This does not negate the Week 12 observation; it addresses a different assessment and is accompanied by substantial uncertainty.

The record does not report results for most listed secondary outcomes or details necessary to evaluate multiplicity and missing data. Therefore the posted results should be understood as limited evidence about the recorded comparisons, rather than a complete answer to every question about treatment effects. No treatment recommendation follows from these registry data alone.

15. Why This Trial Matters Statistically

This trial is statistically notable because its record combines a randomized comparison with a crossover design and an unmasked assignment. Those design features make the timing and sequence of treatment especially relevant to understanding the outcome contrast. The registry identifies the design but does not report the sequence or the analysis needed to assess how crossover was handled.

The primary endpoint is a binary threshold applied to a biological measurement. This offers a clear, clinically interpretable question, but it also compresses continuous HBV DNA values into a yes-or-no classification. The Week 12 arm percentages and their interval estimate allow readers to distinguish the observed contrast from its precision, while the unadjusted p-value alone would not communicate the size or uncertainty of the effect.

The record also illustrates why results at different time points should be interpreted with attention to how each arm is defined. The Week 48 comparator includes both adefovir and entecavir in its label, unlike the Week 12 comparator description. Without treatment sequence and period details, the later result cannot be assumed to represent the same direct contrast.

Finally, the registry lists a broad range of secondary outcomes, but most do not have posted results. Without those results, multiplicity information, and a complete analysis plan, readers cannot assess the overall consistency of evidence across endpoints. The limitations arise from what is and is not documented in the registry record.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry identifies a crossover model but does not report treatment sequence, treatment periods, washout procedures, or the statistical model used for the primary comparison. These details are needed to understand how the Week 12 arm comparison relates to the crossover design. The arm labels also differ across the Week 12 and Week 48 outcome descriptions, and the record does not explain that difference.

The primary outcome counts are 89 in the entecavir arm and 77 in the adefovir arm, while enrollment is recorded as 228. The registry does not explain the relationship between enrollment and the outcome counts, nor does it report missing outcome counts or reasons for exclusion from the analysis. Masking is listed as none, and the record does not describe measures to reduce assessment or reporting bias.

Only the Week 48 HBV DNA secondary result is accompanied by a posted comparison in the record. Results for the other listed secondary outcomes are not reported in the registry record. The registry also does not state how multiple endpoints were handled, whether an adjusted analysis was performed, or the method used for confidence intervals and p-values. These gaps restrict assessment of robustness and precision.

The safety information is limited to event counts and a serious-event term. Exposure duration, event timing, treatment attribution, and a reported death count are unavailable. The findings should therefore be interpreted as the registry’s recorded outcomes, with important uncertainty about analysis, follow-up, and reporting rather than as a complete account of the trial.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Suboptimal Responders to Adefovir Switching to Entecavir — NCT00718887.
• Registry record last updated 2013-02-11; status last verified 2013-01.
• Results first posted 2013-02-11.
• 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

NCT00718887 is titled Suboptimal Responders to Adefovir Switching to Entecavir. The official title describes a comparison of Week 12 antiviral efficacy and safety of switching to entecavir versus continuing adefovir in adults with chronic hepatitis B and a suboptimal response to adefovir. The registry lists Bristol-Myers Squibb as sponsor, Phase 4, randomized allocation, no masking, and a crossover model. Enrollment is 228, and status is completed.

The primary outcome is the percentage with HBV DNA below 50 IU/mL at Week 12 by polymerase chain reaction testing. The record reports 5.6% in the entecavir arm and 0.0% in the adefovir arm, with an unadjusted p-value of 0.035. A Week 48 secondary comparison is also posted; results for most other listed secondary outcomes are not reported in the registry record. The recorded study start is 2008-07 and primary completion is 2009-12.