A Study of Peginterferon Alfa-2a With or Without Ribavirin in Participants With Chronic Hepatitis D (CHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Peginterferon Alfa-2a With or Without Ribavirin in Participants With Chronic Hepatitis D (CHD) (NCT02731131), a randomized phase 2 study. The primary outcome is Number of Participants With Alanine Aminotransferase (ALT) Normalization Plus Negative Hepatitis D Virus (HDV) Ribonucleic Acid (RNA) at 48 Weeks After End of Treatment.

2. Clinical Question

The endpoint requires both components: ALT must meet the registry’s definition of normalization, and HDV RNA must not be detected by PCR. A participant meeting only one component would not meet the combined endpoint as described. The registry reports 0 participants meeting it in the monotherapy group and 1 participant in the combination group. These are small group counts, so the result is chiefly a description of what occurred among the analyzed participants; it does not by itself settle whether the treatments differ in the broader population.

3. Trial Design

This was a Phase 2, randomized, parallel-group, open-label, single-center pilot study of peginterferon alfa-2a with or without ribavirin in participants with chronic hepatitis D. The registry identifies Hoffmann-La Roche as the sponsor. It lists the study as completed, with a start date of 2004-09 and a primary completion date of 2009-05.

Participants were assigned to one of two groups: peginterferon alfa-2a alone, or peginterferon alfa-2a plus ribavirin. Both regimens were described as lasting 48 weeks. The registry reports 12 participants enrolled and 6 participants per group for the primary outcome results. The study was open-label, meaning masking was not used according to the registry. Details of the randomization sequence, allocation concealment, and any procedures used to limit bias are not reported in the registry record.

The primary outcome was a participant count for the combined finding of ALT normalization plus negative HDV RNA at Week 96. This assessment was 48 weeks after the end of treatment. The record also lists five secondary outcomes involving ALT normalization, negative HDV RNA, or their combination at end of treatment and at follow-up. The primary endpoint analysis is reported for the ITT Population.

The record describes the study as a pilot but does not report a sample-size justification or a planned target for detecting a specified treatment difference. It also does not report the number screened, the number who discontinued treatment, or participant-level follow-up completion. Those omissions limit assessment of recruitment and retention in this small trial.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT Population.

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.

Population: Intent-to-Treat (ITT) Population: All participants who received at least one dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Alanine Aminotransferase (ALT) Normalization Plus Negative Hepatitis D Virus (HDV) Ribonucleic Acid (RNA) at 48 Weeks After End of Treatment, measured over Week 96.

The primary endpoint counts participants who met two conditions at Week 96: ALT normalization and negative HDV RNA. Week 96 is identified as 48 weeks after the end of treatment. ALT normalization was defined for participants whose baseline ALT was above the upper limit of normal: their ALT had to be at or below the upper limit of normal at Week 96. Negative HDV RNA meant that HDV RNA was not detected by PCR.

This is a combined endpoint: success requires both the biochemical criterion and the virologic criterion. The count therefore does not describe ALT or HDV RNA in isolation. The registry lists these components separately among the secondary outcomes at other assessment times, which can help distinguish a combined response from the individual outcomes, but results for those endpoints are not included in the registry record for this analysis.

Using a participant count makes the outcome directly interpretable as the number meeting the stated definition in each group. The registry reports 0 participants in Group A and 1 participant in Group B. Because the outcome is binary at the participant level—meeting or not meeting the combined definition—the comparison uses a method suited to categorical counts. The small group sizes make the observed counts especially important to describe alongside the test result. The endpoint definition does not, by itself, indicate whether any observed finding persisted beyond the specified follow-up assessment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: A binary outcome records whether each participant meets a defined condition or does not. For this primary outcome, the condition combines ALT normalization and negative HDV RNA at Week 96. The results are reported as participant counts, rather than as a continuous measurement such as an ALT concentration.

Why use Fisher’s exact test?

General statistical explanation: Fisher’s exact test evaluates the association between group assignment and a binary outcome using the observed counts. It is often used when group sizes or event counts are small, because its calculation does not rely on the same large-sample approximation used by some other categorical-data tests. The registry reports this test for the comparison between the two treatment groups. Its reported p-value is 0.30.

The p-value is a measure calculated under a null hypothesis of no association between group and outcome, using the test’s assumptions. It describes the compatibility of the observed data with that null hypothesis; it is not a measure of effect magnitude or a probability that one treatment is superior. The registry record does not state a significance threshold or give an interval estimate for the comparison. The p-value should therefore be considered alongside the underlying counts and the limited sample size, rather than as a standalone conclusion.

Counts and precision

General statistical explanation: An effect estimate describes the magnitude of a contrast between groups; a confidence interval describes uncertainty around such an estimate under the analysis assumptions. When counts are sparse, estimates can be imprecise, and a confidence interval can communicate that uncertainty more directly than a p-value alone. No confidence interval or effect estimate is reported for this primary comparison in the registry record. No new estimate is calculated in the posted results described by these registry entries.

The reported counts—0 participants meeting the endpoint in Group A and 1 in Group B—remain the clearest direct description of the observed outcome. They do not imply that the underlying probability of meeting the endpoint is exactly zero in one group or exactly known in the other. In a small study, observed counts can vary substantially across samples, and the registry does not provide an interval to quantify that uncertainty.

Randomization and open-label conduct

General statistical explanation: Random assignment is intended to make treatment groups comparable on average, including for factors that are not measured. In a small trial, randomization does not guarantee balance on every participant characteristic. Open-label conduct means treatment assignment was not masked; knowledge of assignment can affect care, reporting, or assessment in some settings. The endpoint includes laboratory-defined components, but the registry record does not describe who assessed outcomes or whether laboratory assessments were blinded. It also does not report allocation concealment or the randomization procedure, so those design details cannot be evaluated from this record.

Analysis population and missing information

The primary outcome is identified as analyzed in the ITT Population. General statistical explanation: An intention-to-treat approach generally aims to analyze participants according to their randomized assignment, but the exact handling of missing outcome measurements must be specified to understand how it was applied. The registry record does not describe missing-data rules, imputation, or how participants without a Week 96 assessment were handled. It also does not report participant flow or the number with missing outcome data.

The record lists 6 participants in each group for the primary result, but does not provide a separate account of treatment exposure, withdrawal, or endpoint availability. As a result, the relationship between enrollment, follow-up, and the analysis counts cannot be assessed in detail. These details matter because incomplete follow-up can affect the interpretation of a participant count, particularly when the outcome is measured after treatment has ended.

Multiplicity and other outcomes

The registry lists six outcome measures in total, including the primary outcome and five secondary outcomes. General statistical explanation: When several outcomes are tested, the chance of obtaining at least one apparently unusual result can increase if each test is considered separately. Trial protocols may address this through a hierarchy or other multiplicity procedure. Whether such an approach was planned or applied is not reported in the registry record. The primary comparison should be distinguished from the separately listed secondary outcomes, whose results are not included in the registry record for this analysis.

The methods information available supports a narrow account: a randomized, open-label, two-group comparison of participant counts, assessed with Fisher’s exact test. Further details about the planned statistical analysis, sample-size justification, interim analyses, missing-data handling, and multiplicity adjustment are not reported in the registry record.

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("Group A: Monotherapy With Peginterferon Alfa-2a", "Group B: Combination With Peginterferon Alfa-2a + ")
n      <- c(6, 6)
events <- c(0, 1)
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  Group A: Monotherapy With Peginterferon Alfa-2a  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Group B: Combination With Peginterferon Alfa-2a +   6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s comparison as a Fisher exact test, with p = 0.30, for the primary endpoint. The associated observed counts are 0 participants meeting the endpoint in the monotherapy group and 1 in the combination group, with 6 participants in each group.

No recalculated comparison or recalculated effect estimate is available in the posted results for this binary endpoint. The registry record provides no confidence interval for the primary comparison. Accordingly, the sponsor’s reported test is the available inferential result; there is no separate recalculation to place alongside it. The record does not flag a discrepancy between the reported analysis and a recalculation.

Fisher’s exact test assesses the observed allocation of binary outcomes between groups under its statistical assumptions. Its p-value does not quantify the treatment contrast or its precision. The counts remain essential context, particularly given the small number of participants. The posted result should not be read as showing equivalence, and it does not establish a dependable difference between the groups. No additional interpretation of the sponsor’s analysis can be made without details of the prespecified analysis plan, the handling of missing outcomes, and any multiplicity procedures, which are not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures: the primary combined ALT and HDV RNA outcome and five secondary outcomes. The secondary outcomes cover ALT normalization and negative HDV RNA, individually or together, at end of treatment and at follow-up. The posted primary comparison is reported separately from those outcomes.

General statistical explanation: Testing several outcomes can create a multiplicity issue: when each test is considered on its own, the overall chance of at least one apparently notable result can be larger than for a single test. Common approaches include prespecifying a primary outcome, ordering tests, or adjusting inference across multiple comparisons. Which approach, if any, was planned or applied is not reported in the registry record. The record does not report a statistical analysis plan, a multiplicity adjustment, or an outcome-testing hierarchy beyond identifying the primary endpoint.

The primary endpoint is described as analyzed in the ITT Population. The record does not explain how this population was defined in practice or how missing Week 96 measurements were handled. It does not report whether missing values were treated as endpoint failures, imputed, excluded, or addressed by another method. The number of participants with missing outcome data and the amount of follow-up by group are not reported in the registry record. Although the primary results list 6 participants per group, this alone does not explain participant flow or confirm how all randomized participants contributed to the endpoint analysis.

The registry record also does not report interim analyses, stopping rules, or a sample-size justification. These details affect how the analysis should be understood, but their absence does not establish that a particular procedure was or was not used. Without the planned analysis details and missing-data accounting, the primary comparison can be described as reported, but its full analysis context cannot be reconstructed.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety figures report 6 participants at risk for serious adverse events in each group and 0 participants affected by serious adverse events in each group. No serious adverse event terms are listed. For other adverse events, the record reports 6 participants at risk and 6 affected in each group. These figures are counts, not estimates of comparative risk, and the record does not provide a statistical comparison of safety outcomes.

The serious-event count of 0 in each group means no participants are recorded as affected among the participants listed at risk. It does not establish that serious events are impossible or that the groups have identical safety profiles. With 6 participants per group, the observed counts provide only a limited description of events in this trial. The record does not provide event-level detail, severity or relationship assessments, or timing for the serious events; no serious event terms are listed.

The other-adverse-event figures indicate that all 6 participants in each group were recorded as affected. The registry entries do not specify the event terms or clarify the classification represented by “other” in these counts. Deaths are listed as null, which means death counts are not reported in the registry record; it should not be interpreted as a reported count of zero. These safety counts should be read separately from the efficacy endpoint and do not establish a treatment recommendation.

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

The posted result establishes a narrow descriptive finding: at Week 96, 1 participant in the peginterferon alfa-2a plus ribavirin group and 0 participants in the peginterferon alfa-2a monotherapy group met the combined endpoint of ALT normalization and negative HDV RNA. There were 6 participants in each group in the primary outcome results. The reported Fisher exact test has p = 0.30.

This result does not establish that the two regimens are equivalent. Equivalence requires a design that defines what degree of difference would count as acceptably similar, and such a margin is not reported in the registry record. Nor does the observed count establish a dependable benefit for either regimen. The small group counts and absence of an effect estimate or confidence interval leave the size and precision of any difference unclear.

The result also applies only to the combined endpoint and its specified assessment at Week 96. It does not provide the results for ALT normalization alone or negative HDV RNA alone at that time, nor does it provide the listed secondary outcome results at end of treatment or follow-up. Those results are not reported in the registry record in the registry record for this analysis.

The record identifies the study as a randomized, open-label pilot study at a single center. Its findings describe this small study and should not be treated as a definitive estimate for all participants with chronic hepatitis D. Details needed to assess generalizability—including participant characteristics, recruitment, treatment completion, and missing follow-up—are not reported in the registry record. The result is therefore best understood as a limited pilot comparison rather than a conclusive judgment about treatment effects or safety.

15. Why This Trial Matters Statistically

This trial is statistically instructive because it illustrates how an apparently simple two-group comparison can be hard to interpret when the outcome is rare and the groups are small. The primary endpoint is a binary combined outcome, and the observed counts are 0 and 1 among groups of 6 participants each. Those counts are more informative as a direct description than as a basis for a strong claim about comparative effects.

The record reports Fisher’s exact test, a method that can be used for categorical outcomes with sparse counts. That choice does not remove the limitations of the underlying information. A test can produce a p-value even when the study has limited precision; the p-value is not an effect-size estimate and does not tell readers how large a treatment difference might be. Here, no effect estimate or confidence interval is reported for the comparison.

The trial also highlights the value of distinguishing an endpoint from its components. Requiring both ALT normalization and negative HDV RNA yields a different question from considering either measure by itself. The registry lists separate secondary outcomes, but their results are not included in the registry record for this analysis. Keeping the combined primary outcome distinct helps prevent a result on one component from being mistaken for success on the other.

Finally, registry reporting details matter. Information about missing outcomes, participant flow, multiplicity, the analysis plan, and sample-size justification is not reported. Without those details, readers can interpret the posted finding accurately but cannot reconstruct the full analysis or assess all sources of uncertainty. The trial therefore demonstrates why transparent reporting of counts, analysis methods, and design decisions is essential when interpreting small pilot studies.

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.

The primary comparison is based on 6 participants per group, and only 1 participant met the combined endpoint across the two groups. Such sparse outcome counts limit the information available about the difference between regimens. The registry reports a p-value but no effect estimate or confidence interval, so the magnitude and precision of a group contrast are not quantified.

The study is described as a single-center pilot and was open-label. The registry record does not report the randomization sequence, allocation concealment, or whether outcome assessors were masked. It also does not provide participant characteristics, screening information, or a detailed account of treatment exposure and discontinuation. These omissions limit evaluation of group comparability and the circumstances in which the results were obtained.

The primary outcome was assessed at Week 96, after the 48-week treatment period and a further 48 weeks after treatment ended. Participant follow-up and missing-outcome handling are not described. The primary analysis is identified as ITT, but the record does not explain how that population was implemented or how missing data were handled. The absence of those details makes it difficult to assess whether the analysis reflects all randomized participants as intended.

The registry lists five secondary outcomes in addition to the primary outcome, but their results and any multiplicity strategy are not reported in the registry record. A sample-size justification, interim analyses, and a detailed statistical plan are also not reported. These limitations constrain interpretation of both the primary efficacy finding and the safety counts; they do not establish that unreported procedures were absent.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Study of Peginterferon Alfa-2a With or Without Ribavirin in Participants With Chronic Hepatitis D (CHD) — NCT02731131.
• Registry record last updated 2016-07-15; status last verified 2016-06.
• Results first posted 2016-07-15.
• 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.

20. Record Summary

NCT02731131 is a completed Phase 2 randomized, open-label, parallel-group pilot study sponsored by Hoffmann-La Roche. It enrolled participants with chronic hepatitis D and compared 48 weeks of peginterferon alfa-2a alone with 48 weeks of peginterferon alfa-2a plus ribavirin. The registry lists a study start of 2004-09 and primary completion of 2009-05.

The primary outcome was the number of participants with ALT normalization plus negative HDV RNA at Week 96. The registry reports 0 of 6 participants in the monotherapy group and 1 of 6 in the combination group meeting the endpoint, with a Fisher exact test p = 0.30. No effect estimate or confidence interval is reported for the comparison. Serious adverse events were recorded for 0 participants in each group; other adverse events were recorded for 6 participants in each group. Death counts are not reported in the registry record.