A Rollover Study of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-experienced Genotype 1 Hepatitis C Infected Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Rollover Study of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-experienced Genotype 1 Hepatitis C Infected Patients (NCT01330316), a non-randomized phase 3 study. The primary outcome is Sustained Virological Response (SVR): Plasma HCV RNA Level < 25 IU/mL.

2. Clinical Question

The central statistical question is descriptive: what SVR12 percentage was observed among the enrolled participants receiving the study regimen? The registry identifies SVR12 as the primary endpoint and reports that the endpoint was expressed as a percentage of participants with a 95% confidence interval. However, the observed percentage and its interval are not reported in the registry record, so the result cannot be quantified from the record.

The study objective included collecting safety and efficacy evidence in people who had previously stopped PegIFN/RBV because of lack of efficacy. That context defines the population and treatment setting; it does not establish that outcomes in this group can be compared causally with outcomes in another group. No randomized comparison is identified.

3. Trial Design

This was a Phase III, open-label, non-randomized, parallel study sponsored by Boehringer Ingelheim. The registry lists enrollment of 119 and status as completed. Participants received BI 201335 once daily for 24 weeks with PegIFN/RBV planned for 24 or 48 weeks. The study concerned treatment-experienced patients with genotype 1 chronic hepatitis C who had failed prior PegIFN/RBV treatment and had been withdrawn for lack of efficacy in earlier trials.

Non-randomized allocation means treatment assignment was not based on random allocation according to the registry record. The study is therefore not a randomized comparison, and the record specifically cautions that arms are not a like-for-like control comparison. Differences between groups, if any are presented in statistical outputs, cannot automatically be attributed to treatment duration or another treatment feature. Differences in participant characteristics or circumstances could also matter, and the information needed to assess such differences is not reported in the registry record.

Open-label means masking was absent. Knowledge of treatment can affect how participants or study staff report, assess, or manage outcomes, particularly outcomes involving judgment or reporting. A laboratory-defined endpoint may be less dependent on subjective assessment, but the record alone does not establish how measurements were collected or adjudicated.

The registry describes the primary endpoint as SVR12, measured 12 weeks after the originally planned treatment duration, and gives a timeframe of up to 60 weeks. The protocol, detailed allocation procedures, actual treatment exposure, adherence, and reasons for any differences from planned treatment are not reported in the registry record. Nor is a detailed account of how the 24- or 48-week combination schedules were assigned reported. These details are important to interpreting any comparison across schedules.

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: Eligible patients who entered the rollover trial within 14 weeks of their last study visit in one of the predecessor trials were not required to do a screening visit (treatment start: Day 1). Eligible patients who were outside of this 14-week window were required to do a screening visit (Visit 1) and started treatment at Visit 2 (Day 1).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS

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: Full analysis set (FAS): This set included all patients who entered the trial, were dispensed study medication, and were documented to have taken at least one dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Sustained Virological Response (SVR): Plasma HCV RNA Level < 25 IU/mL, measured over 12 weeks post treatment, up to 60 weeks.

The primary endpoint is sustained virological response, defined as plasma HCV RNA below 25 IU/mL 12 weeks after the originally planned treatment duration. The registry describes this as SVR12 and identifies the measurement as the percentage of participants meeting that definition. The assessment timeframe is 12 weeks post-treatment, up to 60 weeks.

This endpoint captures whether the specified HCV RNA threshold was met after treatment had ended, rather than only while participants were receiving treatment. In general, a post-treatment endpoint is used to describe whether a response is sustained through the stated follow-up period. It is a virological measure; it does not by itself describe every aspect of health, safety, or quality of life.

The registry specifies a 95% confidence interval for the primary endpoint. In general, a confidence interval conveys uncertainty around an estimated percentage, with its width affected by the amount of information and the variability in the data. The observed SVR12 percentage and interval are not reported in the registry record, so their magnitude and precision cannot be assessed from the registry information available. The registry identifies the primary population as FAS, but the meaning and membership of that population are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a percentage of participants and specifies a 95% confidence interval. It does not report the numerical SVR12 estimate or interval, the analysis methods used to obtain them, or a detailed statistical analysis plan. The concepts below explain how these methods are generally interpreted; they do not establish which procedures were used in this study.

What does a percentage estimate describe?

For a binary endpoint such as meeting or not meeting the SVR12 threshold, a percentage describes the proportion of an analysis population with the event of interest. Its interpretation depends on a clear event definition, the population included in the denominator, and how missing or unevaluable measurements are handled. Here, the event definition is stated, and the primary population is labeled FAS. The definition of FAS, the endpoint denominator, and the handling of unavailable measurements are not reported in the registry record.

A percentage is a descriptive summary of the analyzed participants. It is not, by itself, an estimate of the causal effect of treatment. Estimating a treatment effect generally requires a suitable comparison and assumptions that support interpreting the contrast. This study is non-randomized, and the record cautions that arms are not a like-for-like control comparison. Any group contrast therefore needs particular caution.

What does a confidence interval add?

In general, a confidence interval communicates sampling uncertainty around an estimate. A narrower interval indicates greater precision under the method used; a wider interval indicates less precision. The interval should be read together with the point estimate and the endpoint definition. A confidence interval is not a guarantee that the true value lies within its limits, nor does it describe uncertainty arising from every possible source of bias, measurement error, or missing data.

The registry specifies a 95% confidence interval for the primary endpoint, but no limits or estimate are reported in the registry record. The interval therefore cannot be used to judge precision or to assess compatibility with a particular benchmark. The method used to calculate that interval is also not reported in the registry record.

Why does the design matter to interpretation?

In a randomized study, random assignment can support comparability between groups in expectation. This study is recorded as non-randomized, so that protection is not posted by the allocation method. Differences between participants assigned to different schedules may reflect characteristics associated with assignment, rather than the schedule itself. Statistical adjustment can sometimes address measured differences, but it cannot automatically remove unmeasured confounding. Whether any adjustment was done is not reported in the registry record.

Open-label design means participants and study staff were not masked. In general, this can influence behavior, reporting, follow-up, and outcome assessment. The primary outcome is defined using a laboratory RNA threshold, but the registry does not report laboratory procedures, central assessment, or measures taken to limit assessment bias. The degree to which open-label conduct affected this endpoint therefore cannot be determined from the record.

How should the planning illustrations be read?

General sample-size planning relates a target effect, a chosen significance level, allocation, and an assumed statistical model to the amount of information needed for a planned analysis. The planning assumptions described for the illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is described as a stated fraction of the observed effect. These are planning illustrations based on an observed effect, not the trial’s own design justification. They are not observed power and do not show that the study had a particular probability of detecting an effect.

For time-to-event calculations, the planning description refers to the total number of events using the Schoenfeld method. Other planning outputs are described as participants per arm. The numerical planning outputs and the observed effect used for those illustrations are not reported in the registry record. No calculation should be treated as evidence that the trial was designed or powered in this way; the registry record does not report the study’s sample-size justification.

What does over-dispersion mean in general?

For count outcomes, over-dispersion means observed variability exceeds what a simple model assumes. If a model ignores this extra variability, standard errors may be too small and confidence intervals or tests may appear more precise than warranted. The registry information for this study does not identify a count-model analysis, report an over-dispersion assessment, or describe a statistical model for the primary binary endpoint. This general point is therefore methodological background, not a claim about the analyses performed.

Overall, the registry provides the endpoint definition and selected design details, but not enough detail to reproduce or fully audit the statistical analysis. The analysis plan, estimation procedures, covariate handling, and diagnostics 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("Relapse", "Non-relapse")
n      <- c(43, 75)
events <- c(41, 41)
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  Relapse  43  41  95.3  84.2  99.4  84.5  98.7  84.5  98.6
ARM  Non-relapse  75  41  54.7  42.7  66.2  43.4  65.4  43.4  65.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists SVR12 as the primary endpoint and identifies secondary outcomes including SVR24, early treatment success, ALT and AST normalization at specified times, and adverse-event outcomes. It also records 16 outcome measures and 0 analyses. The registry record does not report a multiplicity strategy, such as a prespecified testing sequence or adjustment for making inferences across multiple outcomes. Without that information, the degree to which secondary findings were intended to support confirmatory claims cannot be assessed.

Missing-data methods are not reported in the registry record. This includes the rules for classifying participants without an endpoint measurement, the treatment of withdrawals, and whether the primary analysis used an observed-case or another approach. These choices can affect a percentage estimate because the denominator and event classification may change with the handling of unavailable outcomes. The record identifies the primary population as FAS, but does not define it or explain how missing observations were handled within it.

Analysis populations beyond the FAS label, including any safety population or per-protocol population, are not defined in the registry record. The statistical analysis plan, endpoint-specific denominators, and any sensitivity analyses are also not reported. These omissions limit the ability to determine how robust an estimate would be to assumptions about missing outcomes or which participants were included.

In general, multiplicity and missing-data decisions should be interpreted alongside the prespecified analysis plan. In this record, the relevant details are not reported, and the numerical outcome analyses are not reported. The absence of these details does not itself establish that a method was or was not used; it means the registry record does not document it.

12. 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: mallory-weiss syndrome (2.3%), hepatic failure (2.3%), pneumonia (2.3%), ascites (1.3%), diarrhoea (1.3%).

The registry lists serious adverse-event fields by relapse status. For the Relapse group, it records 1 affected participant among 43 at risk for serious events and 38 among 43 for other events. For the Non-relapse group, it records 6 affected participants among 75 at risk for serious events and 68 among 75 for other events. These are recorded counts within the listed groups, not randomized treatment comparisons. The registry record does not explain the relationship between these relapse categories and treatment assignment or provide enough context to interpret differences as treatment effects.

The listed top serious adverse-event terms are Mallory-Weiss syndrome, 2.3%; Hepatic failure, 2.3%; Pneumonia, 2.3%; Ascites, 1.3%; Diarrhoea, 1.3%; and Gastroenteritis, 1.3%. The registry record does not provide further detail in this listing about event timing, duration, recurrence, or attribution to treatment. Death counts are not reported in the registry record.

In general, adverse-event percentages depend on the denominator and the event-counting rules. A participant may experience more than one event, so counts of events and counts of affected participants are not interchangeable. These listings describe reported safety events; they do not establish that treatment caused an event or that an event was more or less likely because of a particular treatment schedule.

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

The record establishes that a completed Phase III study evaluated BI 201335 with PegIFN/RBV in treatment-experienced patients with genotype 1 chronic hepatitis C. It specifies SVR12 as the primary endpoint, defines the viral RNA threshold and assessment timing, and identifies a primary analysis population label. It also records secondary outcome topics and selected adverse-event information.

Those details describe what was studied and how the primary outcome was defined. They do not provide the observed SVR12 percentage or confidence interval. Without those results, the registry record cannot establish the level of response observed or how precisely it was estimated. The record also does not document enough analysis detail to assess the handling of missing outcomes, the definition of FAS, or the statistical procedures used.

The study’s non-randomized, open-label design is important. The registry cautions that arms are not a like-for-like control comparison. Any differences between groups should therefore be treated as descriptive unless supported by a suitable analysis and assumptions that address confounding. Such adjustment methods and their results are not reported in the registry record. The design does not by itself show that the regimen caused a particular outcome.

The safety listings give counts and percentages for named categories and serious-event terms. They are not a substitute for a complete account of event timing, severity, attribution, or individual treatment exposure. The registry record does not report those details in the listed information.

In general, a trial’s endpoint definition, design, estimate, uncertainty, and analysis methods all contribute to interpretation. Here, the definition and some design details are documented, but the primary numerical result and important analysis details are not reported in the registry record. No conclusion that treatment works or does not work follows from the information recorded.

14. Why This Trial Matters Statistically

This study illustrates why an endpoint definition and a numerical result are different kinds of information. The registry defines SVR12 precisely as plasma HCV RNA below 25 IU/mL 12 weeks after the originally planned treatment duration. That definition makes the intended outcome interpretable, but it does not reveal how many participants met it. The observed percentage and its 95% confidence interval are not reported in the registry record.

It also illustrates the importance of design when interpreting group differences. A non-randomized study can describe outcomes in the participants treated, but allocation does not create the protection against confounding associated with random assignment. The registry explicitly cautions that arms are not a like-for-like control comparison. Consequently, a contrast across groups would require careful interpretation and transparent adjustment methods, which are not reported in the registry record.

The treatment context is also statistically relevant: participants had failed prior PegIFN/RBV and were withdrawn from earlier trials because of lack of efficacy. Results in such a population would answer a question about that setting, not necessarily about other populations. The registry’s stated objective and eligibility context clarify the intended scope, while the actual endpoint result remains unavailable in the registry record.

Finally, this record highlights the value of reporting analysis populations, missing-data methods, and multiplicity decisions alongside results. The endpoint population is labeled FAS, but its definition and missing-data rules are not reported. The record lists secondary outcomes but does not document a multiplicity strategy. Together, these gaps limit reproducibility and the extent to which statistical certainty can be evaluated, even when an endpoint has been clearly specified.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting efficacy is that the registry record does not report the observed primary endpoint percentage or its 95% confidence interval. The primary endpoint can therefore be described, but its result and precision cannot be assessed from the record. Values for the listed secondary outcomes are also not reported in the registry record.

The non-randomized allocation limits causal interpretation of comparisons between groups. The registry cautions that arms are not a like-for-like control comparison. The information needed to judge group comparability, assignment to the 24- or 48-week PegIFN/RBV schedules, or adjustment for relevant differences is not reported in the registry record. Open-label conduct may also affect reporting or assessment, while details of outcome measurement and bias mitigation are not reported.

The record identifies FAS as the primary population but does not define it. Endpoint denominators, missing-data rules, analysis populations for safety outcomes, and sensitivity analyses are not reported in the registry record. The statistical analysis plan, multiplicity approach, and sample-size justification are likewise not reported. Planning illustrations are not substitutes for a documented design justification or observed results.

The safety information is limited to selected counts and listed serious-event terms. Further context about timing, attribution, repeated events, and treatment exposure is not reported in the registry record. These limitations concern what can be concluded from the registry information; they do not establish what may have been collected or analyzed outside the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Rollover Study of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-experienced Genotype 1 Hepatitis C Infected Patients — NCT01330316.
• Registry record last updated 2016-06-30; status last verified 2016-05.
• Results first posted 2015-07-31.
• 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

NCT01330316 is a completed Phase III, open-label, non-randomized, parallel study sponsored by Boehringer Ingelheim, with enrollment of 119. It examined once-daily BI 201335 for 24 weeks with PegIFN/RBV planned for 24 or 48 weeks in treatment-experienced patients with genotype 1 chronic hepatitis C who had failed prior PegIFN/RBV and were withdrawn for lack of efficacy.

The primary endpoint was SVR12: plasma HCV RNA below 25 IU/mL 12 weeks after the originally planned treatment duration. The primary population is labeled FAS. The observed endpoint result and confidence interval are not reported in the registry record. The record lists secondary virological, laboratory, and safety outcomes, but their results and the statistical analysis details needed to interpret them are not reported in the registry record.