Combination Therapy for Chronic Hepatitis C Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Therapy for Chronic Hepatitis C Infection (NCT01805882), a non-randomized phase 2 study. The primary outcome is The Proportion of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs.

2. Clinical Question

3. Trial Design

This was a completed Phase 2 pilot study with non-randomized allocation, no masking, and a parallel-group design. The registry lists enrollment as 229 and identifies chronic hepatitis C as the condition under study. The listed start was 2013-01, and primary completion was 2015-08. Those dates describe the record’s timeline; they do not provide information about the timing of analyses or any interim review.

The arms varied in both regimen and eligibility characteristics. Some evaluated sofosbuvir and ledipasvir for 12 weeks, while others added GS-9669 or GS-9451 and used shorter treatment durations. Further arms included participants with genotype 4, prior treatment experience, advanced liver disease, early-stage liver disease, or previous treatment failure within another study arm. These distinctions matter for interpretation: the arms do not differ only by drug combination.

Because assignment was non-randomized, the study does not establish a randomized comparison between regimens. Treatment groups may differ in their underlying participant characteristics, and the record does not report an adjustment strategy that would account for such differences. The open-label design also means masking was absent, although the primary outcome was defined by a laboratory threshold. The registry record does not report a protocol-based sample-size justification, a detailed statistical analysis plan, or interim-analysis plans. Those omissions limit assessment of how the design and analyses were selected.

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.

Only the first 6 of 9 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Subjects who received treatment drugs per arm as listed in the Outcome Measure Description

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.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Proportion of Subjects Who Achieve Sustained Viral Response (SVR12) 12 Weeks After the Stop of Treatment Drugs, measured over 12 weeks after stop of treatment.

The primary endpoint was the proportion of treated participants with sustained viral response 12 weeks after stopping treatment. Response was defined using serum HCV RNA: a concentration below 43 IU/mL, the lower limit of quantification. In statistical terms, this is a binary outcome for each participant—response or no documented response under the endpoint definition—summarized as a proportion within an arm.

SVR12 is used as a follow-up measure because it asks whether viral RNA remains below the specified measurement threshold after treatment has ended, rather than only while treatment is being taken. The 12-week assessment interval is part of the endpoint definition. The registry record’s outcome description specifies that the population consists of subjects who received treatment drugs per arm, but it does not provide the number assessed for the endpoint, the number meeting the response definition, or the arm-level proportions.

A percentage alone would describe the observed frequency in the assessed group; a confidence interval would convey uncertainty around that estimate. The record specifies a 95% confidence interval as the dispersion measure, but no endpoint estimates or confidence limits are posted. Consequently, the endpoint is defined, but its observed magnitude and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is binary: each participant either meets the stated SVR12 definition or does not meet it based on the available endpoint assessment. For a binary outcome, the basic descriptive summary is the proportion of participants with the event of interest among those included in the analysis. In this study, the event of interest is response, defined by serum HCV RNA below 43 IU/mL 12 weeks after treatment stops. The registry record gives this definition but does not report the response counts or proportions.

What would a confidence interval convey?

In general, a confidence interval describes the uncertainty around an estimated quantity, such as an arm-specific response proportion. It reflects that an estimate from a group of participants is not necessarily the exact underlying proportion for a broader population. A narrower interval indicates greater precision under the method used; a wider interval indicates more uncertainty. The registry specifies a 95% confidence interval, but does not report the intervals themselves or the method used to calculate them. No precision comparison between arms can therefore be made from the registry record.

Why does the allocation matter?

Random allocation is one way to balance participant characteristics across treatment groups on average. This study was non-randomized, so the treatment groups may differ before treatment begins. Here, the arm descriptions explicitly distinguish groups by genotype, prior treatment, liver disease status, regimen, and treatment duration. These features can complicate comparisons: an outcome difference between arms may reflect differences in who entered each group as well as differences in treatment. Statistical adjustment can sometimes address measured differences, but the registry record does not report an adjusted primary analysis or the variables it would use.

What can be learned from a proportion?

As a general matter, an observed proportion describes the fraction of analyzed participants meeting an outcome definition. It does not by itself explain why the outcome occurred, establish that a treatment caused it, or show whether a contrast between groups is statistically or clinically meaningful. Assessment of a group contrast would require the arm-level results, their uncertainty, and an analysis appropriate to the study design. Those primary results are not reported in the registry record.

How should planning calculations be read?

The stated planning assumptions describe an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They also describe planning for a stated fraction of the observed effect. In general, such calculations ask how much information a future study might need under specified assumptions. They are not the trial’s observed power, and they do not establish that the study was designed around those assumptions. The numerical planning results and a protocol-based sample-size justification are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion means that observed variation is greater than a statistical model would expect under its assumptions. When relevant to an analysis, ignoring it can make uncertainty appear smaller than it is. This endpoint is described as a binary proportion, but the registry record does not report an over-dispersion assessment, a model for the outcome, or a method for comparing arms. It would therefore be inappropriate to infer that an over-dispersion adjustment was used or needed.

The registry reports one primary outcome measure and no analysis entries. That does not establish that no analysis was conducted; it means that analysis results are not reported in the record used for this interpretation. The record also does not specify a multiplicity adjustment, a missing-data method, or details of the analysis population beyond the description of subjects receiving treatment drugs per arm. These gaps prevent a fuller audit of the statistical methods.

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("A: HCV GT-1, tx Naive, 12 Wks Sofosbuvir/Ledipasvi", "B: HCV GT-1, tx Naive, 6 Wks Sofosbuvir/Ledipasvir", "C: HCV GT-1, tx Naive, 6 Wks Sofosbuvir/Ledipasvir", "D Retx: HCV GT-1, Re-Treatment, 12 Wks Sofosbuvir,", "D: HCV GT-1, Tx-relapsed, 12 Wks Sofosbuvir/Ledipa", "E: HCV GT-4, tx Naive/Expd, 12 Wks Sofosbuvir/Ledi")
n      <- c(20, 20, 20, 34, 14, 21)
events <- c(20, 19, 19, 31, 14, 20)
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  A: HCV GT-1, tx Naive, 12 Wks Sofosbuvir/Ledipasvi  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9
ARM  B: HCV GT-1, tx Naive, 6 Wks Sofosbuvir/Ledipasvir  20  19  95.0  75.1  99.9  76.4  99.1  76.2  98.8
ARM  C: HCV GT-1, tx Naive, 6 Wks Sofosbuvir/Ledipasvir  20  19  95.0  75.1  99.9  76.4  99.1  76.2  98.8
ARM  D Retx: HCV GT-1, Re-Treatment, 12 Wks Sofosbuvir,  34  31  91.2  76.3  98.1  77.0  97.0  76.9  96.8
ARM  D: HCV GT-1, Tx-relapsed, 12 Wks Sofosbuvir/Ledipa  14  14  100.0  76.8  100.0  78.5  100.0  78.2  99.8
ARM  E: HCV GT-4, tx Naive/Expd, 12 Wks Sofosbuvir/Ledi  21  20  95.2  76.2  99.9  77.3  99.2  77.2  98.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies SVR12 as the primary outcome measure, but does not report a statistical analysis plan or explain how multiple comparisons were handled. The study has multiple arms with different combinations, durations, and participant characteristics. If several arm contrasts or outcome questions were tested, multiplicity could affect the interpretation of statistical significance. The record does not state whether the investigators planned a specific comparison hierarchy, adjusted significance thresholds, or treated the arm results as descriptive. No correction method should be inferred.

Missing-data handling is also not reported in the registry record. The primary outcome description refers to subjects who received treatment drugs per arm, but does not explain what happened when SVR12 status was unavailable, when a participant discontinued, or when the RNA measurement was outside the planned assessment. The record does not state whether missing outcomes were excluded, imputed, or assigned a particular response status. Without these rules, the denominator and possible influence of missing follow-up on an endpoint estimate cannot be evaluated.

The record does not describe whether the primary analysis was intention-to-treat, per-protocol, or another analysis population. It names the treated participants per arm in the outcome description, but does not give participant flow into the endpoint analysis or explain exclusions. These details are important because an estimate can depend on which participants are included. The registry record also does not report the analysis methods for comparisons among arms, covariate adjustment, or interim analyses. These are reporting gaps, not evidence that a particular method was or was not used outside the record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: influenza (7.1%), vertigo (5.0%), pain (5.0%), bradycardia (4.0%), angina pectoris (2.9%).

The safety record lists serious adverse events by arm as the number of participants at risk and the number affected. For arm A, it reports 0 affected among 20 at risk; for arm B, 0 among 20; for arm C, 2 among 20; for D Retx, 1 among 34; for arm D, 1 among 14; for arm E, 0 among 21; for arm F, 2 among 50; for arm G, 0 among 25; and for arm H, 1 among 25. These are participant counts, not a measure of treatment effect. The registry record does not report deaths; a null death entry should not be read as a reported count of zero.

The listed serious event terms and percentages are Influenza, 7.1%; Vertigo, 5.0%; Pain, 5.0%; Bradycardia, 4.0%; Angina pectoris, 2.9%; and Colitis, 2.0%. The record does not provide enough detail to assign these listed percentages to particular arms or to interpret their denominators beyond what is stated. Event counts across non-randomized arms are not like-for-like comparisons, particularly because the groups differ in their characteristics and regimens. The figures describe reported observations; they do not establish that a drug caused an event or support a causal safety ranking.

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

The central statistical meaning of the record is that the study was designed to assess SVR12 across several hepatitis C treatment regimens, but the registry record does not report the primary endpoint results. It specifies the outcome threshold and follow-up time, yet gives no arm-level response counts, proportions, or confidence intervals. The principal efficacy question therefore cannot be answered quantitatively from the posted results.

Even if arm-level percentages were available, this design would require cautious interpretation. Allocation was non-randomized, and the arms differ in participant characteristics and treatment regimens. A contrast would not automatically represent a causal treatment effect. It could reflect differences in treatment history, genotype, liver disease status, or other factors related to assignment. The registry record does not report a statistical adjustment that would resolve these concerns.

The safety counts and selected event percentages offer descriptive information, but do not replace the efficacy endpoint and do not support causal conclusions. Counts of affected participants should not be mistaken for total event counts, and the absence of a reported death value should not be converted to zero. The record also lacks details on missing outcome data and endpoint analysis populations, which limits interpretation of any proportion that might otherwise be reported.

Finally, planning illustrations based on an observed effect concern hypothetical study planning under stated assumptions. They are not evidence about the probability that this completed study detected an effect, and they are not observed power. No treatment recommendation follows from these registry data. The defensible conclusion is about what the record reports and omits: a defined primary endpoint and trial design are available, while the primary response estimates and their precision are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because it places several regimens and clinically distinct groups within a non-randomized parallel design. That structure can be useful for describing outcomes across treatment experiences and disease characteristics, but it does not produce the balance expected from randomized allocation. The arm descriptions make clear that the comparisons involve more than drug combinations alone: treatment duration, genotype, prior treatment, and liver disease status also vary.

The primary outcome is clearly defined by both its timing and laboratory threshold. That definition is essential for reproducibility: a response is tied to serum HCV RNA below 43 IU/mL, measured 12 weeks after treatment stops. But a defined endpoint is not the same as a reported result. Without counts, proportions, and confidence intervals, readers cannot assess the observed response frequency or its precision. This illustrates why outcome definitions and outcome data must be considered separately.

The record also demonstrates why safety summaries need context. Arm-specific serious-event counts are descriptive, while selected terms are listed with percentages. Neither format alone establishes causal attribution, and differences between non-randomized groups cannot be read as direct treatment comparisons. Clear reporting of denominators, analysis populations, missing-data rules, and inferential methods would help readers judge uncertainty and comparability. Those details are not reported in the registry record. The most important statistical point is therefore the boundary between a rich design description and the absent primary estimates needed to evaluate the study question.

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.

A limitation specific to this record is that it describes a pilot study with multiple arms that differ in regimen, treatment duration, genotype, treatment history, and liver disease characteristics. Since allocation was non-randomized, direct arm contrasts would be vulnerable to confounding by these differences. The record does not report a common randomized comparator or an adjusted analysis that could address measured differences.

The primary outcome is defined, but its results are not reported. No arm-specific SVR12 counts, proportions, or 95% confidence intervals are available in the registry record. The reported enrollment of 229 does not identify the denominator for each endpoint estimate, and the adverse event risk counts should not be treated as endpoint denominators. The outcome description refers to participants who received treatment drugs per arm, but participant flow and the final analysis population are not specified.

Other reporting limitations include the absence of a described missing-data approach, multiplicity plan, detailed statistical analysis methods, and protocol-based sample-size justification. Numerical results for planning illustrations are not present in the record. The record lists selected serious adverse event terms and percentages but does not give enough context to link those percentages to specific arms or establish causal relationships. These omissions limit both reproducibility and the strength of any statistical interpretation. They do not establish that analyses or plans were absent from study conduct; they mean those details are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination Therapy for Chronic Hepatitis C Infection — NCT01805882.
• Registry record last updated 2017-06-08; status last verified 2017-02.
• Results first posted 2017-04-11.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes a completed Phase 2, non-randomized, unmasked, parallel study of combination therapy for chronic hepatitis C, with enrollment listed as 229. The arms evaluated sofosbuvir and ledipasvir, with or without GS-9669 or GS-9451, across differing treatment durations and participant groups. The primary outcome was SVR12, defined as serum HCV RNA below 43 IU/mL 12 weeks after treatment ended, with a 95% confidence interval specified as the dispersion measure.

Arm-level primary outcome results and confidence intervals are not reported in the registry record. Serious adverse event counts are listed by arm, along with selected event terms and percentages; deaths are not reported. The record does not report the primary analysis methods, missing-data handling, multiplicity strategy, or a protocol-based sample-size justification. The design and endpoint can be described, but the primary response estimates and their precision cannot be evaluated from the posted results.