Safety and Efficacy of Sofosbuvir + Velpatasvir With or Without Ribavirin in Treatment-Naive Adults With Chronic HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Sofosbuvir + Velpatasvir With or Without Ribavirin in Treatment-Naive Adults With Chronic HCV Infection (NCT01858766), a randomized phase 2 study. The primary outcome is Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12).

2. Clinical Question

The central outcome is SVR12: whether HCV RNA was below the lower limit of quantitation at the specified post-treatment assessment. The trial also collected information on virologic failure and safety. The treatment groups differ in duration, velpatasvir dose, use of ribavirin, and, for many groups, hepatitis C genotype. Those features define the comparisons that can be made, but they also mean that results across all groups should not be read as though every regimen differed in only one feature.

The registry reports 379 participants enrolled overall. That overall figure does not describe the size of each endpoint group; the primary results list group-specific denominators, which are small in several genotype strata. The study therefore offers estimates within a range of regimens and genotypes, while the interpretation of any contrast depends on which groups are being compared and how their participants were selected.

3. Trial Design

This was a randomized, parallel-group, open-label Phase 2 study. The registry lists Gilead Sciences as sponsor and the study status as completed. The study began in 2013-04, and primary completion was recorded as 2014-05. Its official title describes a multicenter investigation of sofosbuvir plus GS-5816 for 12 weeks in treatment-naive subjects with chronic HCV; the listed study arms also include 8-week regimens and ribavirin-containing groups.

All listed groups received sofosbuvir plus velpatasvir. Participants were assigned to regimens with 25 mg or 100 mg velpatasvir, and the regimen duration varied between 12 weeks and 8 weeks. Group assignment also depended on genotype: the 12-week arms included separate groups for genotype 1, 2, 3, 4, 5, and 6, while the 8-week arms listed genotype 1 and genotype 2 groups. Ribavirin was included in some, but not all, of the 8-week arms. There was no placebo-only or untreated group in the listed arms.

Open-label means treatment assignment was not masked according to the registry. Randomization can support comparisons between assigned groups, but it does not remove the limitations created by small group sizes or by comparing groups that differ in genotype as well as regimen. The registry gives an overall enrollment of 379; the endpoint denominators vary by treatment group and are reported alongside the results.

The record does not report the planned allocation ratio, the randomization procedure, a sample-size justification, interim analyses, or a detailed statistical analysis plan. The posted results identify a full analysis set for the primary outcome, defined as randomized participants who received at least 1 dose of study drug. Whether other analysis populations were planned or used is 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: 469 participants were screened.

Only the first 6 of 19 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set: participants randomized 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: participants who were randomized and received at least 1 dose of study drug.

Only the first 6 of 20 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Sustained Virologic Response (SVR) 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 discontinuation of study treatment, called SVR12 in the registry. It was assessed at posttreatment week 12. SVR12 was defined as HCV RNA below the lower limit of quantitation, specified as 15 IU/mL, at that assessment. The endpoint therefore records whether a participant met a defined virologic threshold at a defined time after treatment ended.

In general, a binary endpoint reduces each participant’s outcome to one of two categories: meeting or not meeting the stated criterion. Reporting the percentage meeting the criterion makes the result interpretable as the proportion of the analysis group with that outcome. It does not, by itself, describe the timing of changes during treatment or after it, nor does it provide a complete account of safety or other clinical outcomes.

SVR12 is used as a post-treatment virologic outcome because it assesses whether the specified threshold is met after therapy has stopped, rather than only while treatment is being taken. The endpoint’s definition matters: it is tied to the registry’s threshold and the posttreatment assessment time, and should not be confused with the separately listed SVR4 or SVR24 outcomes. The registry identifies the primary analysis population as randomized participants who received at least 1 dose of study drug. It does not report how missing week 12 measurements were handled, so the outcome percentages should be read within the limits of the recorded population definition and the information available about missing data.

7. Results Posted in the Registry

• SOF+VEL 100 mg 12 Weeks (GT1): 100.0% (28/28) versus 96.3% (26/27) on control; risk difference 3.7 percentage points (95% CI -3.4 to 10.8), risk ratio 1.04 (0.96–1.12); unadjusted two-proportion z-test p = 0.304.
• SOF+VEL 25 mg 12 Weeks (GT2): 90.9% (10/11) versus 96.3% (26/27) on control; risk difference -5.4 percentage points (95% CI -23.8 to 13.0), risk ratio 0.94 (0.77–1.15); unadjusted two-proportion z-test p = 0.500.
• SOF+VEL 100 mg 12 Weeks (GT2): 100.0% (10/10) versus 96.3% (26/27) on control; risk difference 3.7 percentage points (95% CI -3.4 to 10.8), risk ratio 1.04 (0.96–1.12); unadjusted two-proportion z-test p = 0.537.
• SOF+VEL 25 mg 12 Weeks (GT3): 92.6% (25/27) versus 96.3% (26/27) on control; risk difference -3.7 percentage points (95% CI -15.9 to 8.5), risk ratio 0.96 (0.84–1.09); unadjusted two-proportion z-test p = 0.552.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants With Virologic Failure

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • SOF+VEL 100 mg 12 Weeks (GT1): 0.0% (0/28) versus 3.7% (1/27) on control; risk difference -3.7 percentage points (95% CI -10.8 to 3.4); unadjusted two-proportion z-test p = 0.304.
  • SOF+VEL 25 mg 12 Weeks (GT2): 0.0% (0/11) versus 3.7% (1/27) on control; risk difference -3.7 percentage points (95% CI -10.8 to 3.4); unadjusted two-proportion z-test p = 0.518.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SOF+VEL 100 mg 12 Weeks (GT1) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SOF+VEL 25 mg 12 Weeks (GT2) and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists SVR4 and SVR24 as secondary outcome concepts, along with virologic failure. However, the posted secondary results include percentages for virologic failure, while SVR4 and SVR24 values are not reported in the registry record. The registry identifies virologic failure as assessed up to posttreatment week 24. These outcomes are related to the primary virologic response question, but they are not interchangeable: SVR12 is the primary threshold-based outcome at a defined post-treatment time, whereas virologic failure is separately listed as an event outcome over a stated period.

Across the groups with posted virologic failure percentages, the pattern is not uniform. Some groups have a reported value of 0.0%, while others have nonzero percentages, with variation across genotype and regimen. The small group sizes mean that a zero observed percentage should not be interpreted as evidence that the underlying event risk is zero. Likewise, differences in percentages across groups are descriptive unless supported by an appropriate comparative analysis.

The broad secondary pattern can be considered alongside the primary results as additional context about outcomes after treatment. It does not independently settle how the primary response percentages should be interpreted. A participant-level relation between SVR12 and virologic failure is not reported, and the registry does not provide a detailed analysis connecting these outcomes.

In general, secondary outcome analyses are often less definitive than the primary analysis, especially when many outcomes or group comparisons are considered. Unadjusted p-values can increase the chance of finding an apparently notable result by chance when many hypotheses are examined. The registry does not report a multiplicity strategy or a complete statistical analysis plan, so any unadjusted secondary comparisons should be treated as exploratory rather than as confirmatory evidence. The reported secondary percentages are best read as descriptive results that complement, but do not replace, the primary SVR12 assessment.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
• Percentage of Participants With Virologic Failure

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant either met the registry’s SVR12 definition or did not. The reported percentage is the proportion meeting that criterion within each listed group. In general, binary outcomes are commonly described with proportions because the scale has a direct interpretation. A proportion does not reveal why a participant did or did not meet the endpoint, and it does not account for other outcomes unless those are analyzed separately.

What does a confidence interval communicate?

A confidence interval describes the uncertainty around an estimated quantity under the assumptions of the method used to calculate it. In general, a wider interval signals less precision, while a narrower interval signals more precision. It is not a range that guarantees where the true value lies, and it is not a probability statement about the individual participant. The registry reports 95% confidence intervals for the primary group percentages. Several are wide, especially where the group denominator is small; intervals extending from a low value to 100.0% indicate that the data are compatible with a broad range of underlying percentages.

The primary results are percentages with confidence intervals, not a model-adjusted comparison across all regimens. That distinction matters. A group-specific interval quantifies uncertainty about that group’s percentage. It does not on its own test whether two groups differ, and overlapping or nonoverlapping intervals are not a substitute for a prespecified comparative analysis. The registry’s posted comparison calculations use risk differences and unadjusted p-values for selected comparisons.

How should risk differences be read?

A risk difference is the first group’s event proportion minus the reference group’s event proportion, according to the comparison’s coding. For SVR12, the outcome is a favorable virologic status, so a negative difference means the compared group’s observed percentage was lower than the reference percentage in that calculation. A confidence interval for a risk difference that includes zero is compatible with no difference under the calculation’s assumptions; an interval that does not include zero indicates the data are less compatible with exactly zero under those assumptions. This is not proof of a causal effect or of practical importance.

For example, the genotype 2 25 mg 8-week comparison has a posted calculated risk difference of -0.194 and a 95% confidence interval from -0.371 to -0.017. The unadjusted p-value is 0.037. These numbers describe that calculation relative to the designated reference arm. The reference is the genotype 1 25 mg 12-week group, so genotype differs between the arms in that comparison. Consequently, the calculation cannot be interpreted as isolating the effect of shortening treatment or changing dose.

What do the p-values add?

In general, a p-value summarizes how unusual data at least as discrepant as those observed would be under a specified null hypothesis and statistical model. It does not measure the probability that the null hypothesis is true, the size of an effect, or the clinical importance of a difference. The displayed comparison p-values are unadjusted. The registry does not report whether these comparisons were prespecified or how multiplicity was addressed, so they warrant cautious interpretation, particularly across numerous arms and outcomes.

What are the planning illustrations?

The sample-size illustrations are not observed power and are not the trial’s own documented design justification. They use the observed effect as a starting point and show hypothetical participants per arm for 80% power and 90% power under stated assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustrations also consider planning for 75% or 50% of the observed effect. In general, using a smaller target effect requires a larger sample to detect it under otherwise fixed assumptions. Because the starting effect comes from small groups and may be unstable, these figures should be read as planning scenarios, not as a definitive sample-size recommendation or retrospective measure of trial adequacy.

The registry record does not report the trial’s sample-size justification, whether the actual design used those assumptions, or whether any interim analyses were conducted. It also does not report a detailed method for handling missing primary endpoint data. These absences limit the ability to assess how the posted calculations relate to the original statistical plan.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable on average, including on factors that may not have been measured. That benefit applies most directly to comparisons among groups randomized within the same relevant population and design. Here, treatment groups are separated by genotype and regimen, and the designated common reference is a genotype 1 group. A calculation comparing that reference to a genotype 2 group cannot be understood as a randomized comparison of regimen alone. Randomization does not remove the interpretive problem created by differences in the groups being contrasted.

11. Confidence Intervals and Precision

The 95% confidence intervals are central to reading the SVR12 percentages. A point estimate gives the observed percentage in the group, while its interval conveys how uncertain that estimate is. For the genotype 1 25 mg 12-week arm, the estimate is 96.3% among 27 participants and the interval is 81.0% to 99.9%. The genotype 1 100 mg 12-week arm has an estimate of 100.0% among 28 participants and an interval of 87.7% to 100.0%. Neither point estimate alone describes the range of values compatible with the data under the calculation.

Precision varies markedly across groups. The genotype 5 arm contains 1 participant, and its interval runs from 2.5% to 100.0%, despite the observed estimate of 100.0%. The genotype 6 groups have 4 and 5 participants, with intervals of 39.8% to 100.0% and 47.8% to 100.0%. Such wide intervals show that the apparent certainty suggested by a high percentage is not matched by much information about the underlying group percentage.

The same issue applies to comparisons. A risk difference interval gives uncertainty about the difference calculated between two groups; a wide interval can include meaningfully different values in either direction. For many posted contrasts, the interval includes zero. One calculated contrast has an interval from -0.371 to -0.017, but it compares genotype 2 with the genotype 1 reference and is unadjusted. The numerical interval should therefore be considered alongside the group definitions and the absence of reported multiplicity methods.

In general, confidence intervals do not correct for small sample size, group differences, missing outcomes, or multiple comparisons. They quantify sampling uncertainty under the calculation’s assumptions. Here, the small genotype-specific denominators and limited description of the analysis plan mean that precision is only one part of the uncertainty. The interval is most informative when read with the denominator, endpoint definition, and comparison context.

12. Multiplicity, Missing Data and Analysis Populations

The primary endpoint population is defined as the full analysis set: participants randomized into the study who received at least 1 dose of study drug. That definition clarifies who was eligible for the primary analysis, but it does not explain how every randomized participant was handled or how missing post-treatment measurements were classified. The registry record does not report the number of missing SVR12 assessments, the reasons for missingness, or the method used to handle missing outcome data.

Missingness can matter for a percentage endpoint because the result depends on which participants contribute to the numerator and denominator and how unavailable outcomes are treated. In general, excluding participants with missing outcomes can produce a different estimate from classifying them under a specified rule. Without a reported missing-data approach and group-specific missingness information, it is not possible to evaluate how sensitive the posted percentages are to unobserved outcomes. No assumptions about missing outcomes should be inferred from the endpoint population definition alone.

The record also lists many regimen and genotype groups and more than one outcome. The posted comparison p-values are unadjusted, and a multiplicity adjustment procedure is not reported in the registry record. In general, testing many hypotheses without adjustment makes at least one small p-value more likely even if no real differences exist. This matters especially when comparisons are selected from a collection of arms and secondary outcomes. The unadjusted results can describe the particular calculations, but their evidential weight is limited when the comparison set and analysis plan are not documented.

A detailed statistical analysis plan, the planned hierarchy of outcomes, prespecified contrasts, and any interim analyses are not reported in the registry record. Nor is a sample-size justification reported. These are not grounds for assuming that no plans existed; they mean only that the record does not document them. The reported percentages and calculations should therefore be interpreted as posted, with uncertainty about the original confirmatory framework and missing-data handling.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: calculus urinary (1.8%), appendicitis (1.8%), electrocardiogram st segment elevation (1.8%), major depression (1.8%), cholecystitis acute (1.3%).

The serious adverse event figures are reported for six broader regimen groups, rather than separately for each genotype-specific efficacy arm. The groups list 77 participants at risk for serious events in each 12-week dose group, 56 in the 25 mg 8-week group, 55 in the 25 mg plus ribavirin group, 55 in the 100 mg 8-week group, and 57 in the 100 mg plus ribavirin group. The corresponding counts with a serious event are 2, 1, 3, 1, 0, and 0, respectively. These are descriptive counts; they do not establish that a regimen caused or prevented an event.

The registry also lists serious event terms and percentages, including Calculus urinary, Appendicitis, Electrocardiogram ST segment elevation, and Major depression at 1.8%, and Cholecystitis acute and Rib fracture at 1.3%. The terms should be understood as reported event categories, not as evidence of a treatment relationship. The record does not provide enough detail in these figures to evaluate event timing, duration, severity beyond the serious classification, or attribution.

Deaths are not reported in the registry record. The counts should be read in the context of the group denominators and the study’s overall size. Small counts provide limited precision, and absence of a reported event in a group is not evidence that the underlying risk is zero. The safety data complement the efficacy outcomes but do not support a definitive comparative safety ranking.

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

The posted results establish what was observed in the listed analysis groups: the percentages meeting the SVR12 definition, the group denominators, and confidence intervals around those percentages. Many 12-week groups have high observed percentages. The intervals, however, are wide in several groups, especially where the denominators are small. That distinction matters: a high point estimate is a description of the observed participants, while the interval communicates substantial uncertainty about the corresponding underlying percentage.

The results do not establish that a particular dose, duration, or addition of ribavirin caused a difference. Some comparisons use a genotype 1 reference group for contrasts with other genotypes, so those comparisons combine differences in genotype and regimen. Even where an unadjusted interval excludes zero, that result does not by itself establish a general treatment effect, particularly when the analysis plan and multiplicity approach are not reported.

These findings also do not establish how SVR12 relates to SVR4, SVR24, later outcomes, or individual participants’ clinical course. The registry record does not report SVR4 or SVR24 results in the posted secondary outcome data. It likewise does not provide enough information to infer effects beyond the outcomes and follow-up periods stated in the registry.

In general, randomized trials can provide useful comparative evidence when the comparisons are well-defined and the analysis is appropriate. In this study, randomization is a design strength, but small genotype-specific groups and differing group characteristics constrain some comparisons. No medical advice follows from these statistical summaries. The most defensible interpretation is limited to the posted estimates and their uncertainty, without translating them into a broader claim that one regimen is effective, ineffective, safer, or preferable.

15. Why This Trial Matters Statistically

This trial is statistically instructive because it combines multiple regimen features with genotype-specific groups. Dose, treatment duration, ribavirin use, and genotype vary across the arms. That structure makes the group-by-group percentages useful for describing what was observed, but it complicates the interpretation of contrasts that might otherwise be mistaken for the isolated effect of one treatment feature.

The spread in group denominators also illustrates why percentages should not be read without their confidence intervals. A 100.0% estimate in a group with 1 participant is not comparably precise to a similar estimate in a group with dozens of participants. Wide intervals communicate that distinction more directly than the point estimate alone. The same principle applies to zero observed virologic failures and to the small serious adverse event counts.

The registry’s common reference is a genotype 1 group, while some calculated contrasts involve other genotypes. This makes clear that a numerical comparison can be correctly calculated yet remain difficult to interpret as a causal regimen effect. Statistical estimates do not solve design comparability problems simply by being accompanied by a p-value or confidence interval.

Finally, the record illustrates the importance of transparency about multiplicity, missing data, and analysis plans. Without a documented strategy, unadjusted results across many groups and outcomes deserve caution. The sample-size illustrations are also distinct from the original design rationale and do not measure observed power. Together, these issues show why good statistical interpretation requires more than ranking point estimates: it requires attention to the question each contrast actually answers and how much information supports it.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several limitations are specific to interpreting these results. First, the primary outcome groups are small for many genotypes. Some strata contain only a handful of participants, so their point estimates are imprecise and their confidence intervals broad. A high percentage in a small group should not be generalized as though it were a stable estimate for a larger population.

Second, the listed regimens do not vary one feature at a time across a single common population. The groups differ by genotype, dose, duration, and, in some cases, ribavirin. Comparisons to the designated reference arm can therefore mix differences in regimen with differences in genotype. This is especially important for the posted calculations comparing genotype 2 groups against the genotype 1 reference.

Third, the study was open-label, and the registry does not describe masking. The primary endpoint is based on an HCV RNA threshold, but the record does not provide detailed information about laboratory procedures or endpoint assessment beyond its definition. The registry also does not report how missing endpoint data were handled or how many measurements were missing.

Fourth, the available comparison results are unadjusted, and a multiplicity approach, prespecified contrast list, and complete analysis plan are not reported in the registry record. Secondary outcome information is incomplete for the listed SVR4 and SVR24 outcomes; their results are not reported in the registry record. The safety figures are aggregated into broader regimen groups and do not establish causal attribution. These limitations constrain the scope and precision of conclusions that can be drawn from the posted data.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Efficacy of Sofosbuvir + Velpatasvir With or Without Ribavirin in Treatment-Naive Adults With Chronic HCV Infection — NCT01858766.
• Registry record last updated 2018-11-14; status last verified 2016-07.
• Results first posted 2016-09-15.
• 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

NCT01858766 is a completed, randomized, open-label, parallel-group Phase 2 study sponsored by Gilead Sciences. It enrolled 379 treatment-naive adults with chronic hepatitis C. The study evaluated sofosbuvir plus velpatasvir at different doses and durations, with or without ribavirin, across genotype-specific groups.

The primary outcome was SVR12, defined as HCV RNA below 15 IU/mL at posttreatment week 12. The primary analysis population included randomized participants who received at least 1 dose of study drug. Posted results show group-specific percentages with 95% confidence intervals; precision varies and is limited in several small groups. The record also reports virologic failure and serious adverse event counts. A detailed statistical analysis plan, sample-size justification, interim analyses, multiplicity strategy, and missing-data handling are not reported in the registry record.