Safety and Efficacy of Ledipasvir/Sofosbuvir in Adults With Chronic HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Ledipasvir/Sofosbuvir in Adults With Chronic HCV Infection (NCT02472886), a non-randomized phase 3 study. The primary outcome is Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12).

2. Clinical Question

3. Trial Design

This was a Phase 3b, multicenter, open-label, parallel-group study. Allocation was non-randomized, and masking was absent. The registry lists enrollment of 153 and a completed study. The listed study start was 2015-06-17, with primary completion on 2016-03-30.

The treatment groups were formed around different clinical histories and characteristics, rather than through random assignment. One group comprised treatment-naive participants with genotype 1 HCV infection without cirrhosis and received LDV/SOF for 8 weeks. A second group had the same treatment-naive genotype 1 and cirrhosis criteria, with HIV-1 coinfection, and also received LDV/SOF for 8 weeks. A third group comprised participants with genotype 1 or 3 infection who had failed to achieve SVR12 in Gilead Study GS-US-334-0119; they received LDV/SOF plus RBV for 12 weeks.

These groups are not interchangeable comparators. Prior treatment, coinfection status, eligible genotypes, and treatment regimens differ across them. Because allocation was non-randomized, observed differences between groups could reflect those differences or other factors, not only the treatment received. The record does not describe a randomized control group or a prespecified between-group causal comparison.

The study’s primary objectives were to evaluate antiviral efficacy, safety, and tolerability. SVR12 was the primary endpoint, with secondary outcomes addressing SVR at other post-treatment times, on-treatment HCV RNA, change in HCV RNA, virologic failure, and HIV-related measures among coinfected participants. Numerical primary outcome results and analysis estimates 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.

Before assignment: 169 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included participants who were enrolled into the study and received at least 1 dose of 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.

Population: Safety Analysis Set included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12), measured over Posttreatment Week 12.

The primary endpoint was the percentage of participants with sustained virologic response 12 weeks after discontinuing therapy, or SVR12. The registry defines response as HCV RNA below the lower limit of quantitation 12 weeks following the last dose of study drug. The primary measurement is therefore a binary status for each participant at a specified post-treatment time, summarized as a percentage in the analysis population.

SVR12 is used as a virologic endpoint because it records whether HCV RNA is below the assay’s quantitation threshold at a defined time after treatment has ended. It is distinct from an on-treatment measurement: the assessment occurs after the final dose, rather than while medication is being taken. This timing makes the endpoint a measure of post-treatment virologic status at the stated follow-up point.

The registry identifies the Full Analysis Set as the population for the primary endpoint. It includes participants enrolled in the study who received at least 1 dose of study drug. The registry record does not report the number of participants in this analysis set, the number who met the SVR12 definition, or the resulting percentage and confidence interval. Consequently, it is not possible from the record to describe the observed response level or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint and design can be understood using several basic statistical ideas. The record defines SVR12 as a binary outcome: at the specified follow-up time, a participant either meets the HCV RNA criterion or does not. A group-level percentage summarizes the share of the analysis population meeting that criterion. The registry record does not report the underlying outcome counts or the percentage, so there is no observed estimate to interpret.

What does a confidence interval express?

The primary endpoint lists a 95% confidence interval as its measure of dispersion. In general, a confidence interval communicates uncertainty around an estimated quantity. For a percentage, its width depends in part on the amount of information available and on how often the outcome occurs. A narrower interval indicates greater statistical precision than a wider interval, but neither width nor interval location can be evaluated without the reported estimate and bounds. Although the endpoint description specifies a 95% confidence interval, its numerical limits are not reported in the registry record.

A confidence interval is not a guarantee that the true value lies within a particular calculated interval, and it is not a measure of the probability that a treatment works. It is an interval produced by a statistical procedure with stated long-run properties under its assumptions. Assessing those assumptions would require details of the analysis and the data, which are not reported in the registry record.

Why does the allocation method matter?

In general, randomization is used to reduce systematic differences between treatment groups at the point of assignment. This study used non-randomized allocation. Its groups were defined by different clinical characteristics, including prior treatment, HIV-1 coinfection, and eligible HCV genotype. Those design features mean that the groups should be described separately rather than treated as equivalent arms in a controlled comparison. If group outcome estimates were available, a crude difference could reflect differences in group composition as well as differences in treatment. The registry record does not report an adjusted analysis that would address this concern.

The study is described as parallel-group, meaning the treatment groups are separate rather than a crossover in which participants receive multiple regimens in sequence. Parallel assignment does not itself establish comparability. Because assignment was non-randomized, the design does not provide the same protection against confounding that randomization is intended to provide.

What does an open-label design imply?

Open-label means that masking was absent. As a general matter, knowledge of treatment can affect expectations, reporting, follow-up, and decisions about care or assessment. The primary endpoint is based on HCV RNA relative to a laboratory quantitation threshold, which is more objective than a participant-reported symptom. Still, the endpoint definition alone does not explain laboratory procedures, handling of measurements, or whether assessment was conducted consistently across groups. Those details are not reported in the registry record.

How should a binary endpoint be read?

A percentage for a binary endpoint needs both a numerator and a denominator: the number meeting the response criterion and the number included in the calculation. The registry defines the primary analysis population as participants enrolled and given at least 1 dose of study drug, but does not report the endpoint counts or the numerical percentage. A percentage without its denominator can be difficult to judge for precision; in this case, neither the percentage nor its denominator is available in the record.

General statistical practice also distinguishes the observed estimate from the precision around it. The estimate describes the result in the analyzed participants; a confidence interval describes uncertainty associated with estimating a broader underlying response proportion. Neither should be confused with a causal treatment effect in a non-randomized comparison. The registry record does not report an analysis estimate, uncertainty interval, or model for the primary outcome.

What can be inferred from the safety counts?

The safety entries distinguish serious adverse events from other adverse events and list participants at risk and affected in each group. In general, a count of participants with an event is not necessarily a count of every event episode, because one participant may experience more than one event. The registry record does not specify event-level detail or provide an inferential comparison. The reported counts should therefore be interpreted as descriptive entries rather than comparative estimates of risk.

Rates can be useful when groups have different amounts of exposure, but the record does not provide exposure-adjusted rates or enough detail to derive them. No new rates or contrasts can be inferred from the listed entries without making calculations that are not reported as registry results. The safety information also should not be substituted for the missing SVR12 efficacy result.

What do planning calculations mean?

Planning sample sizes are illustrations of how much information a future study might need under stated assumptions. The record describes an illustration based on the observed effect, two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect. Such planning quantities are not outcomes observed in this study and are not observed power.

The numerical planning results and the observed effect are not reported in the registry record. The planning assumptions also do not establish that the original study used those assumptions: the sample-size description explicitly concerns a planning illustration, not the trial’s own design. The record does not report the original sample-size justification, statistical plan, or interim-analysis plan. Without those details and the numerical outcome estimates, the planning framework cannot be used to reconstruct the study’s analysis or to evaluate its precision.

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("LDV/SOF 8 Weeks (TN, HCV-monoinfected)", "LDV/SOF 8 Weeks (TN, HCV/HIV-coinfected)", "LDV/SOF + RBV 12 Weeks (TE, SOF-treated, HCV-monoi")
n      <- c(67, 59, 27)
events <- c(67, 57, 26)
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  LDV/SOF 8 Weeks (TN, HCV-monoinfected)  67  67  100.0  94.6  100.0  94.6  100.0  94.7  100.0
ARM  LDV/SOF 8 Weeks (TN, HCV/HIV-coinfected)  59  57  96.6  88.3  99.6  88.5  99.1  88.5  99.0
ARM  LDV/SOF + RBV 12 Weeks (TE, SOF-treated, HCV-monoi  27  26  96.3  81.0  99.9  81.7  99.3  81.7  99.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary SVR12 endpoint and several secondary outcome topics, including SVR4 and SVR24, HCV RNA during treatment, change in HCV RNA, virologic failure, and HIV-related measures for coinfected participants. Testing multiple outcomes can raise a multiplicity issue: in general, when many hypotheses are examined, the chance of at least one nominally positive result can increase. A prespecified testing hierarchy or adjustment can address that issue, but the statistical plan and any multiplicity strategy are not reported in the registry record.

The registry record does not report numerical results or analyses for the primary endpoint. It also does not describe how missing SVR12 measurements were handled, whether participants without an evaluable post-treatment measurement were counted as nonresponders, or whether any sensitivity analyses were conducted. These choices can affect the interpretation of a percentage endpoint, so the absence of a stated approach limits assessment of the analysis.

The Full Analysis Set is defined as enrolled participants who received at least 1 dose of study drug. The record does not provide the number in that set or explain how exclusions, withdrawals, or missing outcome assessments were treated. The registry also does not report an analysis population for each secondary endpoint. Therefore, it is not possible to determine from this record whether denominators were consistent across outcomes or how incomplete follow-up affected the reported results.

The record lists 8 outcome measures and 0 analyses. It does not report a statistical analysis plan, interim analyses, or a sample-size justification for the trial. Those items should be considered unreported rather than assumed absent from the conduct of the study.

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 safety entries list participants at risk and participants affected by serious and other adverse events in each treatment group. For serious adverse events, the affected count is 0 in all three groups. The record also lists 0 deaths in all three groups. For other adverse events, the affected counts are 5 in the LDV/SOF 8 Weeks treatment-naive HCV-monoinfected group, 2 in the LDV/SOF 8 Weeks treatment-naive HCV/HIV-coinfected group, and 8 in the LDV/SOF plus RBV 12 Weeks retreatment group.

These are descriptive counts. They do not establish that the groups had equal safety, because the groups differ in composition and treatment, and allocation was non-randomized. The record does not give event-level descriptions, severity categories for other adverse events, exposure-adjusted rates, or a statistical comparison. A zero serious-event count in the registry entry should not be read as proof that a regimen has no risk, and the other-event counts should not be interpreted as causal differences between regimens.

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

This registry record is useful for identifying the study question, treatment groups, endpoint definition, and selected safety entries. It establishes that the study evaluated LDV/SOF, with or without RBV, in adults with chronic HCV infection, and that SVR12 was its primary endpoint. It also makes clear that the groups differed in clinical characteristics and that treatment assignment was non-randomized.

The record does not report the numerical SVR12 result, its confidence interval, or the denominator used for the primary endpoint. It therefore cannot establish the observed response proportion or how precisely that proportion was estimated. A stated endpoint and study objective are not substitutes for a reported result.

Nor can the three groups be read as a randomized comparative trial. Their eligibility characteristics and regimens differ, and there is no like-for-like control comparison identified in the record. Even if group outcomes were available, direct contrasts would require caution because treatment assignment was not randomized. The registry record does not provide adjusted comparisons that could address differences between groups.

The safety counts offer limited descriptive information: the serious adverse event and death entries are zero in each group, while other adverse events affected participants in every group. These entries do not provide a complete characterization of safety, and they do not support claims of equivalence or comparative safety.

Accordingly, the record supports conclusions about the study’s design and intended measurements, but not a numerical conclusion about SVR12 or a causal conclusion about treatment benefit or harm. Missing outcome results and analysis details should be treated as unreported in the registry record, not filled in through assumptions.

14. Why This Trial Matters Statistically

This study illustrates why a trial’s allocation method and group definitions matter when interpreting clinical results. A parallel design can include several treatment groups, but non-randomized assignment means those groups may differ for reasons tied to eligibility or clinical history. Here, the groups were distinguished by prior treatment, HIV-1 coinfection, HCV genotype eligibility, and treatment regimen. Those distinctions are central to deciding whether a comparison is meaningful.

The record also shows the importance of separating an endpoint definition from an endpoint result. SVR12 is clearly defined by HCV RNA below the lower limit of quantitation 12 weeks after the last dose, and the primary analysis population is described. Yet no numerical SVR12 result or confidence interval is reported. Without the estimate and its uncertainty, readers cannot assess the level or precision of the measured outcome.

Safety entries require similar care. Counts for serious adverse events, other adverse events, and deaths answer different descriptive questions. A zero count in one category does not mean no adverse events of any kind, and counts from groups with different characteristics do not establish comparative risk.

Finally, the record distinguishes planning illustrations from a trial’s own design and analysis. Sample-size planning based on an observed effect is not observed power, and it does not reveal the original design rationale. The sample-size justification, analysis plan, missing-data approach, and multiplicity strategy are not reported in the registry record. Together, these omissions limit what can be inferred from the record, even though it documents the clinical question and endpoint framework.

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 primary limitation for interpreting efficacy is that the registry record does not report the numerical SVR12 result, its confidence interval, or the outcome denominator. Although SVR12 is designated as the primary endpoint and defined clearly, its observed level and precision cannot be evaluated.

The non-randomized design limits between-group interpretation. Treatment groups differ in eligibility characteristics, including prior treatment history, HIV-1 coinfection, HCV genotype, and regimen. They are not like-for-like control groups, so a direct comparison would be vulnerable to confounding. The open-label design is also relevant to assessment and reporting, although the primary endpoint is based on a laboratory measure.

Important analysis details are not reported in the registry record. These include the statistical analysis plan, original sample-size justification, interim-analysis plan, missing-data handling, and any multiplicity strategy. The record does not give numerical primary or secondary outcome analyses, or describe how incomplete follow-up was handled.

The safety information is limited to group counts for serious adverse events, other adverse events, and deaths. Event descriptions, exposure-adjusted rates, detailed severity information, and comparative statistical analyses are not reported. These limits mean the safety counts should be treated as descriptive, not as a full or comparative assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Ledipasvir/Sofosbuvir in Adults With Chronic HCV Infection — NCT02472886.
• Registry record last updated 2018-11-16; status last verified 2017-03.
• Results first posted 2017-05-10.
• 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 describes a completed Phase 3b, multicenter, open-label, non-randomized, parallel-group study of LDV/SOF, with or without RBV, in adults with chronic HCV infection. The treatment groups differed by prior treatment history, HIV-1 coinfection, and HCV genotype eligibility. The primary endpoint was the percentage with SVR12, defined as HCV RNA below the lower limit of quantitation 12 weeks after the last dose.

The Full Analysis Set included enrolled participants who received at least 1 dose of study drug. The registry record does not report the numerical SVR12 result, its confidence interval, or a statistical comparison. Safety entries list zero serious adverse events and deaths in each group, alongside other adverse events affecting participants in each group. Missing-data handling, the statistical plan, and the original sample-size justification are not reported in the registry record.