Ledipasvir/Sofosbuvir for Hepatitis B Virus Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ledipasvir/Sofosbuvir for Hepatitis B Virus Infection (NCT03312023), a randomized phase 2 study. The primary outcome is Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment..

2. Clinical Question

The study rationale refers to observed HBsAg declines in people with both hepatitis B and hepatitis C who received ledipasvir/sofosbuvir for hepatitis C. The trial’s hypothesis was that a similar decrease might occur in people with hepatitis B alone. That rationale motivates the question; it is not evidence that the treatment produced the hypothesized change in this study.

3. Trial Design

This completed Phase II study was open-label, randomized, and used a parallel-group design. The registry lists enrollment of 21 participants and a study period from 2018-02-01 to primary completion on 2020-08-10. Masking was listed as none, so participants and study personnel were not blinded according to the registry description.

Four treatment groups are reported. Group A received ledipasvir/sofosbuvir for 12 weeks and was described as having low-replicative HBV. Group B received the same combination for 12 weeks and was described as having virally suppressed HBV. Group C received sofosbuvir alone for 12 weeks, and Group D received ledipasvir alone for 12 weeks; both were described as low-replicative HBV. The registry specifically states that Groups C and D were randomized 1:1. Details of the allocation process, including how participants were assigned to the other groups, are not reported in the registry record.

The primary outcome is the change in serum HBsAg from baseline to the end of 12 weeks of treatment. The registry identifies the outcome population as the intention-to-treat population, defined there as all subjects who received at least one study drug. This definition is reported as written; further details about exclusions, withdrawals, or how participants with missing measurements were handled are not reported in the registry record.

The posted arm-level results include 8 participants in Group A, 5 in Group B, 4 in Group C, and 4 in Group D. These group counts add up to the listed enrollment of 21, but the registry record does not explain whether every enrolled participant contributed an evaluable primary-outcome measurement. The planned sample size, the rationale for that size, and any interim analyses 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

Analysis population for the primary outcome, as defined in the registry: Intention to treat population - all subjects who have received at least one 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 Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment., measured over 12 weeks.

The primary endpoint is the change in serum hepatitis B surface antigen (HBsAg), measured in log10 IU/mL, from baseline to the end of 12 weeks of treatment. The registry describes measurements at baseline, during treatment visits, and at week 12, with the primary comparison being baseline to the end of treatment. The listed summary measure is the mean, with standard deviation as the measure of spread.

HBsAg is used because the registry identifies it as a marker of persistent hepatitis B infection. A change in this marker can therefore be used to describe a biological response during treatment. The study presents the endpoint as an indicator of antiviral activity, not as a direct measure of symptoms, complications, or long-term outcomes. Although the study rationale discusses HBsAg decline, the registry record does not specify the sign convention used to encode change in the posted results. The direction of each numeric value should therefore not be inferred from its sign alone.

The endpoint is distinct from functional cure. The registry describes functional cure as HBsAg-to-antibody seroconversion, but the primary endpoint is the change in HBsAg level over the treatment period. A measured change in HBsAg does not by itself establish that seroconversion occurred. The registry does not report a primary-outcome confidence interval or a formal inferential result, so the size and precision of any treatment-group differences cannot be established from the posted endpoint summaries alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a continuous primary outcome summarized by a mean and standard deviation. A mean describes the group’s average observed change, while a standard deviation describes variation among participant measurements around that average. These summaries can convey the central value and spread of the observations, but they do not by themselves estimate a randomized treatment effect. A treatment effect in a comparative trial generally requires a defined contrast between groups, with uncertainty around that contrast.

General statistical context: a confidence interval gives a range of values compatible with the data and the statistical model used to calculate it. It helps show how precisely an effect has been estimated. The registry record does not report confidence intervals for the primary outcome. Without them, the precision of the group means and of any between-group contrast cannot be read directly from the posted results. Standard deviations should not be substituted for confidence intervals: the former describe variability among observations, whereas the latter express uncertainty about an estimated quantity.

The registry describes the trial as randomized, open-label, and parallel-group. Random allocation can support a fair comparison when the groups being compared are assigned under the same randomization process and analyzed as planned. Here, the registry explicitly describes 1:1 randomization for Groups C and D. The allocation procedure for Groups A and B, and whether either group was randomized against another group, are not reported in the registry record. The different HBV states described for Groups A and B also matter when interpreting their arm-level results: differences could reflect characteristics of the groups, not only treatment.

General statistical context: when treatment groups are randomized and comparable, a direct contrast can help separate treatment differences from baseline differences. A before-and-after change within a group answers a different question. It describes change over time among participants receiving that regimen, but without an appropriate comparator it cannot distinguish a treatment-related change from other influences or natural fluctuation. The posted arm means are changes from baseline; the registry does not provide a formal treatment contrast or an adjusted analysis.

The primary endpoint uses a log10 IU/mL scale. General statistical context: a logarithmic scale represents values in terms of their logarithms, which can be useful when measurements span a wide range. Interpretation of a change on such a scale depends on the precise definition and direction of the change. The registry does not state how the difference was calculated or how signs were assigned in the posted results. Therefore, the numerical signs should be reported as listed rather than translated into a direction of biological change.

Variation can also affect how well a mean represents the observations. General statistical context: unusually variable data, skewed distributions, or influential observations can make a mean and standard deviation less representative of the underlying pattern. For count outcomes, over-dispersion means that variation exceeds what a simple count model expects and may require a different variance model. The primary outcome is continuous, and no distributional assessment or model specification is reported in the registry record. Over-dispersion is therefore a general concept, not a reported feature of this endpoint.

The record names an intention-to-treat population and defines it as all subjects who received at least one study drug. The term is used in different ways across trial reports, so the operational definition matters. The registry does not describe whether all randomized participants received treatment, how participants who discontinued treatment were analyzed, or how missing HBsAg measurements were handled. It also does not report the number of outcome measurements available at each visit. These omissions limit assessment of whether the posted summaries represent the intended analysis population.

No primary-outcome analysis details such as a prespecified model, covariate adjustment, hypothesis test, or multiplicity procedure are reported in the registry record. The record lists no posted inferential analyses. This means that the primary endpoint summaries cannot be used to reconstruct an unreported sponsor analysis or to infer the statistical plan. Any additional analysis would require participant-level information and assumptions that are not available in the registry record.

General statistical context: multiple outcomes or multiple comparisons can increase the chance of finding an apparently notable result by chance if each is tested without an appropriate plan. The registry lists one secondary outcome concerning HBV DNA and reports three outcome measures overall, but does not describe how multiplicity was addressed. No correction or hierarchy should be presumed. Likewise, no interim analysis plan is reported, so none should be inferred from the trial’s duration or completion status.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Group A (LDV/SOF for Low Replicative HBV)", "Group B (LDV/SOF for Viral Suppressed HBV)", "Group C (SOF for Low Replicative HBV)", "Group D (LDV for Low Replicative HBV)")
n   <- c(8, 5, 4, 4)
m   <- c(0.39, 0.4, 0.19, -0.05)
sp  <- c(0.2, 0.3, 0.3, 0.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Group A (LDV/SOF for Low Replicative HBV)  8  0.390  0.200  0.223  0.557
CARM  Group B (LDV/SOF for Viral Suppressed HBV)  5  0.400  0.300  0.028  0.772
CARM  Group C (SOF for Low Replicative HBV)  4  0.190  0.300  -0.287  0.667
CARM  Group D (LDV for Low Replicative HBV)  4  -0.050  0.100  -0.209  0.109

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures overall and one secondary outcome: change in serum HBV DNA from baseline to the end of 12 weeks. No secondary-outcome numerical results are included in the posted results summarized for this study. Details of how the primary and secondary outcomes were ordered, how multiple comparisons were handled, or whether any testing hierarchy was prespecified are not reported in the registry record. Without that information, the possibility of multiplicity cannot be evaluated from the reported summaries, and no adjustment procedure should be assumed.

The registry identifies an intention-to-treat population and defines it as all subjects who received at least one study drug. It does not report how this population relates to all randomized participants, whether any participants were excluded from outcome analyses, or how treatment discontinuations were handled. The number of participants with an observed HBsAg value at baseline and at week 12 is not separately reported. The method for handling missing measurements, including whether any imputation was used, is not reported in the registry record.

These gaps matter because an analysis based only on participants with complete measurements can differ from an analysis that includes all participants under a defined missing-data approach. The direction and size of any such difference cannot be determined from the arm summaries. The registry also does not report a statistical analysis plan, interim analyses, or details of the primary-outcome model. As a result, the intended handling of missing data and multiplicity cannot be checked against the posted summaries.

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.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each group, with 0 affected participants in Group A, 0 in Group B, 0 in Group C, and 0 in Group D. It also reports deaths as 0 in every group. These figures describe what was recorded in the registry; they do not establish that no serious events could occur outside the reported observation or reporting framework.

For other adverse events, the registry lists 7 affected participants among 8 at risk in Group A, 2 among 5 in Group B, 4 among 4 in Group C, and 1 among 4 in Group D. These are counts, not comparative estimates adjusted for group characteristics or time under observation. The registry record does not provide event terms for these other adverse events in the information, nor does it state the observation window or give a detailed account of severity and relatedness.

Zero recorded serious events in groups with few participants should be read as an absence of reported events in this study, not proof that a risk is absent. The counts also do not establish that one regimen is safer than another. Differences between group counts may reflect the small group sizes, exposure, or other factors that are not described in the registry record.

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

The results describe mean changes in HBsAg for four groups treated for 12 weeks. They provide a snapshot of the recorded endpoint summaries in this completed Phase II study. The posted numbers are useful for seeing the group-level means and the amount of variation reported as standard deviations, but they do not establish a comparative treatment effect. No primary-outcome confidence intervals, p-values, or formal comparisons are reported in the registry record.

The study’s hypothesis concerned a decline in HBsAg among people with hepatitis B alone, drawing on observations in people with both hepatitis B and hepatitis C. The registry summaries do not, by themselves, confirm that hypothesis. The sign convention for the change values is not reported, and the arms differ in the HBV states described. The only explicitly stated randomized pair is the comparison of sofosbuvir alone with ledipasvir alone in low-replicative HBV; no inferential result for that contrast is posted.

The endpoint is a biomarker measure, not a direct measure of functional cure. The registry defines functional cure in terms of HBsAg-to-antibody seroconversion, while the primary endpoint is change in HBsAg level. The posted primary summaries therefore do not show whether participants achieved seroconversion, whether any change persisted after treatment, or whether clinical outcomes changed. Those outcomes are not reported in the registry record.

These results should not be treated as evidence that a regimen works or does not work. They are descriptive arm-level observations from a small study, without reported uncertainty estimates or a complete account of the analysis. The absence of reported serious adverse events is likewise not proof of no risk. The study’s role is to document the observed biomarker and safety summaries in its enrolled groups; broader conclusions would require evidence and analyses not reported in the registry record.

14. Why This Trial Matters Statistically

This study raises a statistical question about interpreting biomarker changes across groups that are not all described as having the same clinical state. Group A and Group B both received ledipasvir/sofosbuvir, but the registry describes low-replicative HBV in one and virally suppressed HBV in the other. Their means are therefore not automatically a randomized comparison of treatment in equivalent populations. A clear account of allocation and the intended contrasts is essential to distinguish treatment comparisons from descriptive subgroup summaries.

The endpoint also illustrates why a mean change requires context. The registry reports means and standard deviations on a log10 IU/mL scale, but does not specify the sign convention or post confidence intervals. Without a defined direction and uncertainty around the estimate, the numerical summaries alone cannot show how precise an effect is or how well it distinguishes groups.

With 21 participants across four groups, the posted summaries are limited in how much they can establish about variation and comparative effects. This is a general consideration about small samples, not a judgment about the observed values. The registry does not report a sample-size justification, so it is not possible to assess the study’s planning assumptions or intended precision.

Finally, the registry identifies an intention-to-treat population but does not report missing-data handling, formal analysis methods, or multiplicity procedures. Those details affect how readers should interpret a biomarker endpoint and any future secondary-outcome findings. The trial matters statistically because it shows how design details and transparent reporting are needed to move from descriptive measurements to a defensible comparison.

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 registry record leaves several trial-specific details unclear. Although the study is listed as randomized, only the 1:1 randomization of Groups C and D is described. The allocation method and the assignment structure for Groups A and B are not reported in the registry record. Because Groups A and B are described as having different HBV states, their arm summaries should not be read as a direct treatment comparison without further design information.

The primary outcome description says that HBsAg was measured at baseline, during therapy, and at week 12, but only the baseline-to-end-of-treatment change is identified as the primary endpoint. The posted group summaries do not include the number of measurements available at each time, individual trajectories, or a confidence interval. The sign convention for the change is also not reported, which limits interpretation of whether a listed positive or negative value represents a decline.

The registry does not report a statistical analysis plan, model details, an inferential test for the primary endpoint, adjustment for baseline values, or a multiplicity approach. It does not report a sample-size justification, interim analyses, or the method used to handle missing data. The relationship between the stated intention-to-treat population and the participants contributing to each result is not further described.

The registry lists a secondary HBV DNA outcome, but numerical results for that outcome are not included in the posted results. It also does not provide longer-term HBsAg results or seroconversion results. These limitations constrain interpretation to the available arm-level summaries and do not permit conclusions about durability or functional cure.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ledipasvir/Sofosbuvir for Hepatitis B Virus Infection — NCT03312023.
• Registry record last updated 2021-09-20; status last verified 2021-08.
• Results first posted 2021-08-25.
• 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

NCT03312023 is a completed, open-label, randomized, parallel-group Phase II study sponsored by the University of Maryland, Baltimore. Enrollment was 21. The study ran from 2018-02-01 to primary completion on 2020-08-10.

Four groups received ledipasvir/sofosbuvir, sofosbuvir alone, or ledipasvir alone for 12 weeks, with the combination studied in groups described as low-replicative or virally suppressed HBV. The primary endpoint was change in serum HBsAg from baseline to the end of treatment, measured in log10 IU/mL and summarized by mean and standard deviation. The registry reports arm-level results and safety counts, but does not report primary-outcome confidence intervals, formal comparative analyses, missing-data methods, or a sample-size justification.