This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Combination Therapy With LdT Plus Adefovir Versus Adefovir Alone (NCT00376259), a randomized phase 3 study. The primary outcome is The Proportion of Participants Who Experienced Virologic Breakthrough.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00376259 |
| Phase | Phase 3 |
| Condition | Hepatitis B |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 43 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis |
| Results posted | Yes |
2. Clinical Question
Population
People with HBeAg-positive chronic hepatitis B who were lamivudine resistant. The registry record lists hepatitis B as the condition studied.
Intervention
Telbivudine, also called LdT, at 600 mg by mouth plus adefovir dipivoxil at 10 mg by mouth once daily. The planned treatment duration was 96 weeks.
Comparator
Adefovir dipivoxil at 10 mg by mouth once daily for 96 weeks.
Primary question
What proportion of participants experienced virologic breakthrough by Week 96 in each randomized group? The study ended early, and no patients received 96 weeks of treatment, so this primary question could not be assessed.
The clinical comparison was between adding telbivudine to adefovir and using adefovir alone. The primary outcome was the proportion of participants who experienced virologic breakthrough. The record defines breakthrough as a minimum of 1 log reduction from baseline followed by a 1 log increase from nadir on at least 2 consecutive visits, including the last treatment visit.
This question concerns a specific population and treatment comparison; the registry record does not establish that its results apply to other populations or treatment regimens. Although the study was randomized, the early termination prevented the planned Week 96 primary endpoint assessment. The record therefore does not provide an estimate of the relative frequency of breakthrough between the groups or an inferential comparison of the regimens. The trial's stated objective was to compare safety and effectiveness, but its posted results cannot answer the primary efficacy question.
3. Trial Design
The registry record describes a Phase 3, randomized, open-label, multicenter, parallel-group study. Participants were assigned to combination therapy or adefovir monotherapy. Because masking was listed as none, treatment assignment was not blinded according to the registry record. The planned regimens were oral telbivudine 600 mg plus oral adefovir 10 mg once daily, or oral adefovir 10 mg once daily. Both regimens were planned for 96 weeks.
The registry lists an enrollment of 43. The study started in 2007-01, had a primary completion date of 2008-08, and is recorded as terminated. The study was terminated early, and no patients received 96 weeks of treatment. The registry record does not report a reason for early termination.
Randomization is intended to support a fair comparison by distributing participant characteristics between treatment groups on average. It does not, by itself, ensure that a valid treatment comparison can be made when the planned endpoint cannot be assessed. Open-label assignment can also matter when outcomes involve clinical decisions or assessments, although the registry record does not describe any particular influence of unmasked treatment assignment in this trial.
The record includes an intended treatment comparison and several secondary outcome topics, including change in HBV DNA concentration, clinical and laboratory safety criteria, and treatment-emergent HBV resistance mutations associated with virologic breakthrough. However, it lists zero posted analyses. It does not report group-level efficacy estimates or inferential comparisons for these outcomes. In particular, the planned 96-week endpoint is unavailable because treatment ended before any participant reached that time point.
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: One patient was randomized but never received study drug treatment because he was discontinued on the randomization day due to sponsor request.
Overall Study
| Stage | Combination Therapy | Adefovir Monotherapy |
|---|---|---|
| STARTED | 22 | 21 |
| Received Study Drug | 21 | 21 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 22 | 21 |
Reasons for not completing this period:
| Reason | Combination Therapy | Adefovir Monotherapy |
|---|---|---|
| Sponsor request - study termination | 21 | 21 |
| Patient request | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: This study was terminated early and no patients received 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed.
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.
| Characteristic | Unit | Combination Therapy | Adefovir Monotherapy | Total |
|---|---|---|---|---|
| Participants analysed | 22 | 21 | 43 | |
| Age Continuous | years | 36.8 (SD 11.82) | 39.0 (SD 10.93) | 37.9 (SD 11.32) |
| Sex: Female, Male: Female | Participants | 3 | 5 | 8 |
| Sex: Female, Male: Male | Participants | 19 | 16 | 35 |
6. Primary Endpoint
The registry lists the primary outcome as The Proportion of Participants Who Experienced Virologic Breakthrough, measured over 96 Weeks.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Proportion of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint was the proportion of participants who experienced virologic breakthrough by 96 weeks. A proportion is a measure of how many participants in a defined group experienced an event during the period being assessed. The endpoint definition required a minimum of 1 log reduction from baseline, followed by a 1 log increase from the lowest value, or nadir, on at least 2 consecutive visits, including the last treatment visit.
This type of endpoint can be used to describe whether a treatment response that had previously improved subsequently worsened according to a prespecified pattern. Requiring the pattern across consecutive visits can distinguish a sustained change from a single measurement fluctuation. The endpoint definition also ties the assessment to the final treatment visit.
Those features make the timing of assessment essential. The primary objective was to evaluate virologic breakthrough by Week 96, but the study was terminated early and no patients received 96 weeks of treatment. The record therefore states that this objective could not be assessed. Without the planned follow-up, the registry cannot report the intended Week 96 proportion or a valid comparison between the randomized groups for this endpoint. The record does not give a substitute endpoint or an alternate analysis period for evaluating the primary question.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central statistical fact is that the trial did not reach the planned primary endpoint assessment. The primary outcome was virologic breakthrough by 96 weeks, but the registry record says that no patients received 96 weeks of treatment because the study was terminated early. Consequently, the stated primary objective could not be assessed. This is not a finding that breakthrough did or did not occur at the planned time point; it means the record does not establish the Week 96 outcome.
The registry lists zero posted analyses. It does not provide a primary endpoint estimate, a between-group effect estimate, a confidence interval, or an inferential test for the primary outcome. The absence of those results means the magnitude and precision of any treatment difference cannot be evaluated from the record. A confidence interval, in general, describes a range of values compatible with the data and statistical method used; no such interval is reported for the primary comparison.
There are posted safety counts. The serious adverse-event figures list 1 affected participant among 21 at risk in the combination group and 0 among 21 at risk in the adefovir monotherapy group. The registry also lists other adverse-event counts of 14 and 11, respectively, with 21 at risk in each group. These are descriptive counts, not evidence of a statistically reliable difference. The record does not report an inferential safety comparison or explain the meaning of the separate “other” category in more detail. Death counts are not reported.
The registry lists an enrollment of 43, while the displayed adverse-event group denominators are 21 in each arm. The record does not explain this difference. The denominators for the posted safety figures should therefore be read as the denominators attached to those figures, rather than assumed to represent every enrolled participant or the analysis population for an efficacy endpoint.
Randomization was part of the study design, but random allocation cannot compensate for the missing planned endpoint follow-up. Early termination may leave few or no observations at the target time point, and in this study the record explicitly says there were none at 96 weeks. No treatment-effect conclusion for the primary efficacy question is supported by the posted results. The available safety counts describe recorded events in the listed groups, but do not establish comparative safety in a broader population or over the full planned treatment duration.
9. Statistical Methods Explained
What does randomization contribute?
Randomization assigns participants to treatment groups using a chance-based process. In general, this helps prevent systematic selection of participants into one group based on their expected outcomes. It supports an unbiased comparison when outcomes are collected and analyzed as planned, while chance imbalances can still occur. The record identifies the study as randomized but does not report the allocation procedure, the method used to generate the allocation sequence, or whether allocation was concealed before assignment.
The trial was open-label, with masking listed as none. In general, knowledge of treatment assignment can affect behavior, additional care, reporting, or assessment, depending on the outcome. Randomization does not remove all possible influences after assignment. The registry record does not describe whether open-label assignment affected outcome collection in this study, and no specific effect should be inferred.
What does a parallel-group comparison mean?
In a parallel design, participants are assigned to one group and followed under that group’s treatment rather than switching between the trial treatments as part of a crossover design. The planned comparison was combination therapy against adefovir monotherapy. An analysis of such a randomized comparison generally needs outcome information collected under a defined follow-up period and a clear description of which participants are included. The registry record does not report a completed primary endpoint analysis population or the analysis rules for handling participants who did not complete treatment.
Why is endpoint timing important?
An endpoint is the outcome specified for assessing a study question. Here, the primary endpoint was the proportion experiencing virologic breakthrough by 96 weeks, and the definition used measurements across consecutive visits, including the last treatment visit. The timing and visit sequence are therefore part of the outcome definition, not merely administrative details. Since no patients received 96 weeks of treatment, the intended endpoint was not assessable. An earlier observation period would not automatically be equivalent to the specified Week 96 endpoint, and the record does not report an alternative primary analysis.
What can descriptive counts tell readers?
A count reports how many participants in a group were recorded as having an event. A denominator indicates the group size used for that count. The safety entries list 1 serious adverse-event participant among 21 at risk for combination therapy and 0 among 21 at risk for monotherapy. They also list 14 and 11 participants, respectively, for the other adverse-event category, with 21 at risk in each group. Those figures describe the posted records; they do not alone quantify uncertainty or establish whether a group difference is compatible with chance variation.
In general, inferential methods combine the observed data with assumptions to estimate uncertainty or test a hypothesis. For a comparison between groups, an effect estimate describes the direction and size of the observed contrast, while a confidence interval communicates its precision under the chosen method. The registry record reports no inferential analyses, no confidence intervals, and no hypothesis tests for the primary endpoint. It also does not report a statistical method for the safety comparisons.
What is over-dispersion, and is it relevant?
In general, over-dispersion occurs when observed variation in data is greater than a model assumes. It can make standard errors too small and confidence intervals too narrow if the model does not account for that extra variability. Whether a model has over-dispersion is a question about the data structure and chosen analysis. The registry record does not report an inferential model for the primary endpoint or any analysis of over-dispersion. No conclusion about its presence in this trial can be drawn.
What can be said about sample-size planning?
A sample-size calculation is generally a prospective planning exercise based on assumptions about the effect to detect, variability or event frequency, significance level, power, and allocation. It is not a result observed in the trial. The registry record does not report the trial’s own sample-size justification or the assumptions used for its design. It also does not report an observed-power analysis. Any planning illustration based on an observed effect would not establish the power of this terminated study or recover the unobserved Week 96 outcome.
The registry’s status as terminated and its statement that the primary endpoint could not be assessed are more informative about interpretability than a hypothetical sample-size calculation. A planned sample size cannot substitute for the outcome data that were not collected at the planned endpoint time.
10. Multiplicity, Missing Data and Analysis Populations
The study lists a primary endpoint and several secondary outcome topics. These include change from baseline in mean HBV DNA concentration, the percentage of participants meeting specified clinical and laboratory safety criteria, and the proportion with treatment-emergent HBV resistance mutations associated with virologic breakthrough. The registry record lists four outcome measures in total, but it does not provide the inferential analyses for these outcomes.
Multiplicity arises when several outcomes, time points, or statistical comparisons are tested. In general, conducting multiple tests can increase the chance of obtaining at least one apparently notable result by chance. A statistical plan may address this through a prespecified hierarchy, adjustment, or other strategy. The registry record does not report how multiplicity was to be handled. It also does not report the full protocol-specified analysis plan or any completed inferential results for the primary or key secondary efficacy outcomes.
Missing data methods concern how analyses account for outcomes that are not observed. In general, the impact of missingness depends on how much information is absent and why it is absent. Here, the record states that the study ended early and no patients received 96 weeks of treatment. It does not report a method for handling missing primary endpoint data, any imputation procedure, or sensitivity analyses. The record does not describe which participants would have been included in each analysis population.
Because the primary endpoint was not assessable and no analyses are posted, multiplicity and missing-data procedures cannot be evaluated from the registry record. These are not evidence that a particular method was or was not used; the relevant methods are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Combination Therapy | 1 | 21 | 4.8% |
| Adefovir Monotherapy | 0 | 21 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Combination Therapy | 14 of 21 |
| Adefovir Monotherapy | 11 of 21 |
Most frequent serious adverse event terms
| Event term | Organ system | Combination Therapy | Adefovir Monotherapy |
|---|---|---|---|
| Hand fracture | Injury, poisoning and procedural complications | 1 of 21 | 0 of 21 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Combination Therapy | Adefovir Monotherapy |
|---|---|---|---|
| Upper respiratory tract infection | Infections and infestations | 5 of 21 | 8 of 21 |
| Fatigue | General disorders | 1 of 21 | 3 of 21 |
| Hepatic steatosis | Hepatobiliary disorders | 2 of 21 | 2 of 21 |
| Blood creatine phosphokinase increased | Investigations | 3 of 21 | 1 of 21 |
| Nasopharyngitis | Infections and infestations | 3 of 21 | 0 of 21 |
| Rhinitis | Infections and infestations | 1 of 21 | 2 of 21 |
| Abdominal pain upper | Gastrointestinal disorders | 0 of 21 | 2 of 21 |
| Dyspepsia | Gastrointestinal disorders | 0 of 21 | 2 of 21 |
| Cough | Respiratory, thoracic and mediastinal disorders | 2 of 21 | 0 of 21 |
Serious events with the highest arm-level rate: hand fracture (4.8%).
The serious adverse-event entries list 1 affected participant among 21 at risk in the combination therapy group and 0 among 21 at risk in the adefovir monotherapy group. The registry’s top serious adverse-event term is Hand fracture, listed at 4.8%. The record does not provide enough context in these entries to attribute that term to a particular treatment group or to infer a causal relationship.
The registry also lists 14 participants with other adverse events in the combination group and 11 in the monotherapy group, with 21 at risk in each group. These are counts from the posted safety record. The meaning of the “other” category is not further defined in the available outcome description, so it should not be treated as interchangeable with the serious adverse-event category.
These figures are descriptive. They do not include an inferential comparison or uncertainty interval, and the record does not report death counts. The safety denominators also should not be assumed to represent the full enrollment: the registry lists enrollment of 43, while each safety group lists 21 at risk. The reason for that difference is not reported in the registry record. Because the trial ended before the planned 96 weeks of treatment, these counts do not describe a completed 96-week safety follow-up for all participants.
12. What the Result Does, and Does Not, Mean
The posted record establishes the design and planned comparison, but not the primary efficacy result. This was a randomized, open-label, parallel-group Phase 3 study of telbivudine plus adefovir versus adefovir alone in HBeAg-positive participants with lamivudine-resistant chronic hepatitis B. The primary endpoint was virologic breakthrough by Week 96. Early termination meant no patients received 96 weeks of treatment, so the primary objective could not be assessed.
That absence of an endpoint result is not the same as evidence that the treatments had identical outcomes, nor is it evidence that one regimen performed better. Without a reported group comparison and estimate of uncertainty, the direction, size, and precision of a difference cannot be determined from the registry record. A null or nonsignificant result cannot be inferred because no primary inferential analysis is reported.
The posted safety counts can be read as descriptive event counts for the participants and denominators listed. They do not, by themselves, establish a treatment-related effect or a statistically reliable difference. The record does not report inferential safety analyses, death counts, or a full explanation of the denominators. The safety counts also do not cover a completed 96-week treatment period, since no participant reached that duration.
The trial record therefore supports a limited interpretation: it documents a planned comparison, early termination, the inability to assess the primary endpoint, and some safety counts. It does not support conclusions about the comparative effectiveness of the regimens at Week 96 or about their comparative safety over the complete planned treatment duration. This limitation reflects the absence of the planned follow-up and analyses, not a statistical finding in favor of either treatment.
13. Why This Trial Matters Statistically
This trial illustrates why a clearly stated endpoint must be considered together with the time at which it is measured. The primary outcome was defined around virologic breakthrough by Week 96 and required a sequence of measurements through the final treatment visit. When the trial ended before participants reached that period, the primary question could not be answered as planned.
It also demonstrates the difference between a study design and an analysis result. Randomization describes how treatment groups were intended to be formed; it does not guarantee that outcomes will be observed or that treatment effects can be estimated. The record reports a randomized comparison but lists zero analyses and no primary inferential result. The existence of a randomized trial is therefore not, on its own, evidence of a quantified treatment difference.
The case is also a reminder to distinguish event counts from comparative evidence. Safety counts are useful descriptions of what was recorded among the listed participants. Without an analysis that estimates uncertainty and addresses the comparison, those counts should not be treated as proof of a difference. The registry’s adverse-event denominators and its overall enrollment are not identical, and the record does not explain why.
Finally, the record shows why missing analysis details matter. It does not report the trial’s sample-size justification, the procedures for missing data, the analysis populations, or how multiplicity would be handled. These omissions limit the ability to assess the planned statistical strategy. In a terminated trial, the distinction between outcomes that were planned and outcomes that were actually assessed is especially important for keeping interpretation aligned with the available evidence.
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 direct limitation is that the trial was terminated before any participant received 96 weeks of treatment. The primary endpoint was defined at that time point, so it could not be assessed. The registry record does not report an alternative primary endpoint analysis or a replacement follow-up period.
The record lists enrollment of 43 but provides adverse-event group denominators of 21 in each arm. It does not explain the difference or report how many participants contributed to each outcome analysis. The analysis populations and participant disposition by treatment group are not reported in the registry record.
The registry lists zero analyses and does not provide inferential results for the primary or secondary efficacy outcomes. It does not report effect estimates, confidence intervals, hypothesis tests, or details of the statistical analysis plan. The trial’s sample-size justification, handling of missing outcome data, and strategy for multiplicity are also not reported in the registry record. The reason for early termination is not reported.
The study was open-label, with masking listed as none. The record does not describe whether knowledge of assignment affected conduct or outcome assessment. Safety information is limited to the listed counts and a serious adverse-event term; death counts and an inferential safety comparison are not reported. These limitations mean the record cannot establish the intended Week 96 efficacy comparison or a complete safety comparison over the planned treatment duration.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Combination Therapy With LdT Plus Adefovir Versus Adefovir Alone — NCT00376259.
- Registry record last updated 2011-06-30; status last verified 2011-06.
- Results first posted 2011-05-17.
- 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.
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18. Record Summary
The registry record describes a randomized, open-label, multicenter, parallel-group Phase 3 study in HBeAg-positive participants with lamivudine-resistant chronic hepatitis B. It compared planned oral telbivudine 600 mg plus adefovir 10 mg once daily with adefovir 10 mg once daily, each for 96 weeks. Enrollment was 43; the study started in 2007-01, reached primary completion in 2008-08, and is listed as terminated.
The primary endpoint was the proportion experiencing virologic breakthrough by Week 96. The study ended early, and no patients received 96 weeks of treatment, so the primary objective could not be assessed. The registry lists zero analyses. Posted safety counts include 1 serious adverse-event participant among 21 at risk in the combination group and 0 among 21 in the monotherapy group. The record does not report inferential efficacy results or the reason for termination.