Sofosbuvir and Ribavirin in Treatment-Naive and Treatment-Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sofosbuvir and Ribavirin in Treatment-Naive and Treatment-Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (NCT01682720), a 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

The clinical question is about the proportion meeting a specified virologic threshold at a defined follow-up time. It is not a direct comparison of the same treatment duration across the same genotype: the reference group has genotype 2, while the comparison groups have genotype 3, and the latter include different treatment durations. Consequently, differences between these groups combine regimen and population distinctions. The registry record does not establish that those differences can be attributed to treatment duration alone.

3. Trial Design

This was a Phase 3, multicenter, randomized, parallel-group, placebo-controlled study sponsored by Gilead Sciences. The official title describes it as double-blind, while the registry’s masking classification is triple. Which specific people or roles were masked is not reported in the registry record. The study enrolled 421 participants and is recorded as completed. Its start is listed as 2012-09, and primary completion as 2013-10.

The stated purpose was to evaluate the safety, tolerability, and antiviral efficacy of GS-7977 with ribavirin in participants with genotype 2 or 3 HCV infection. The registry lists placebo-matched SOF and placebo-matched RBV among the interventions. The arm descriptions identify placebo for 12 weeks in genotype 2 or 3, SOF for 12 weeks in genotype 2 or 3, and SOF for 24 weeks in genotype 3. The 24-week genotype 3 description specifies SOF 400 mg once daily with weight-based RBV. The 12-week descriptions mention weight-based RBV of 1000-1200 mg daily in divided doses.

The primary endpoint results are broken out by genotype and duration, rather than presented as a single percentage for the whole enrolled population. They include 73 participants in SOF 12 Weeks (GT2), 11 in SOF 12 Weeks (GT3), and 250 in SOF 24 Weeks (GT3). The placebo group is not represented in this primary outcome because its data were not collected for SVR12. The registry record does not report the original sample-size justification, allocation ratios, or the details of the randomization procedure. It also does not explain how treatment-naive and treatment-experienced participants were distributed among the outcome groups.

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: * 475 participants were screened and 421 were randomized. * 419 participants were randomized and received at least 1 dose of study drug (Safety Analysis Set). * 334 participants with genotype 2 or 3 hepatitis C virus (HCV) infection were randomized and received at least 1 dose of sofosbuvir (Full Analysis Set).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set: participants with genotype 2 or 3 HCV infection were randomized and received at least 1 dose of SOF.

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.

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 is the percentage of participants with sustained virologic response 12 weeks after discontinuing therapy, called SVR12. It measures whether HCV RNA was below the lower limit of quantitation 12 weeks after the last dose of study drug. The registry defines that threshold as less than 25 IU/mL. The endpoint is recorded at posttreatment week 12.

In general, a sustained virologic response endpoint describes a laboratory outcome assessed after treatment ends, rather than simply measuring viral RNA while participants are taking study medication. The specified follow-up time makes the assessment comparable across participants who reach that time point. A percentage communicates the share of the analyzed group meeting the registry’s threshold; it does not describe how far below the threshold an individual’s RNA result was.

The Full Analysis Set is defined as participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of SOF. The posted outcome gives response percentages for three SOF groups, but it does not provide primary-outcome data for the placebo group. Thus, these results do not furnish a placebo comparison for SVR12. The registry record also does not report how missing SVR12 measurements were handled or whether any participants were excluded from the endpoint calculation after entering the Full Analysis Set.

7. Results Posted in the Registry

• SOF 12 Weeks (GT3): 27.3% (3/11) versus 93.2% (68/73) on control; risk difference -65.9 percentage points (95% CI -92.8 to -38.9), risk ratio 0.29 (0.11–0.77); unadjusted two-proportion z-test p = <0.001.
• SOF 24 Weeks (GT3): 85.2% (213/250) versus 93.2% (68/73) on control; risk difference -8.0 percentage points (95% CI -15.2 to -0.7), risk ratio 0.91 (0.84–0.99); unadjusted two-proportion z-test p = 0.076.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary result is a binary outcome: each participant either meets the registry’s SVR12 definition or does not. A percentage expresses the number meeting the definition relative to the group size used in the endpoint result. For example, the genotype 2 12-week result is reported as 93.2% for a group of 73, while the genotype 3 12-week result is 27.3% for a group of 11. These are posted percentages, not estimates of how much viral RNA changed within a participant.

What does the risk difference describe?

In general, a risk difference is the difference between two event proportions, expressed on an absolute scale. Here, the event is SVR12. A negative direction for the comparison estimates indicates a lower observed response proportion in the named genotype 3 group than in the genotype 2 reference group. The comparison record reports a risk-difference estimate and a confidence interval for each genotype 3 group. Because the source values have more than three decimal places, the precise interval bounds are not repeated. The counts and posted percentages convey the direction of the contrasts without inventing extra precision.

A risk difference is different from a relative measure such as a risk ratio or odds ratio. It describes an absolute contrast in proportions, while relative measures compare the proportions multiplicatively or compare event odds. These measures answer related but non-identical questions and can give different impressions when baseline proportions are high or group sizes are uneven. The registry includes relative measures in its comparison calculations, but interpreting them does not remove the central design limitation: genotype differs between the reference and comparison groups.

How should the p values be understood?

In general, a p value evaluates how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true, nor the chance that a result arose “by chance.” The posted unadjusted p values are <0.001 for SOF 12 Weeks (GT3) versus the genotype 2 reference and 0.076 for SOF 24 Weeks (GT3) versus that reference. “Unadjusted” means the reported values do not reflect a stated multiplicity adjustment. Whether any adjustment was used for the trial’s sponsor analysis is not reported in the registry record.

The 24-week comparison’s p value and recalculated confidence interval do not give the same simple threshold impression: the interval’s reported bounds are both negative, whereas the p value is 0.076. A confidence interval and a p value will ordinarily align when they are generated by corresponding methods for the same test and confidence level. Different methods or assumptions can yield different summaries. The registry record does not report enough detail to identify the reason for this difference, so it is better to state both summaries than to treat one as a correction of the other.

What does a confidence interval add?

In general, a confidence interval gives a range of values compatible with the data under a specified estimation procedure. It conveys uncertainty in an estimate, not a guarantee that the true value lies within that particular calculated interval. An interval that is wide signals less precision than a narrower interval on the same scale. Precision depends on the amount of information in the data and on the variability of the outcome; for a percentage, group size is especially relevant. The 12-week genotype 3 group has 11 participants, substantially fewer than the 250 in the 24-week genotype 3 group, so its estimate is based on a much smaller group.

The interval for the SOF 12 Weeks (GT3) risk difference is entirely negative, as is the posted interval for SOF 24 Weeks (GT3). These are recalculated, unadjusted contrasts from the posted summary statistics, not a substitute for a full analysis plan. The registry’s own analysis methods, including any covariate adjustment, are not reported in the registry record. In general, adjusted analyses can differ from unadjusted calculations because they account for specified characteristics or use a different statistical model.

Why do the groups matter?

Randomization is a design method intended, in general, to support fair comparison among assigned groups. However, the endpoint comparisons are grouped by genotype and duration, and the posted reference is genotype 2 while the other groups are genotype 3. This structure means that a contrast is not solely a comparison of treatment duration among otherwise matched groups. The registry also does not report enough detail to reconstruct the allocation structure for each genotype or to determine whether any stratification was used.

For a binary endpoint, the number of participants meeting the threshold and the group denominator are both important. A high or low percentage should be read alongside its group size and uncertainty. Counts are especially informative when the denominator is small: the 3 participants meeting SVR12 in the 11-person genotype 3 12-week group correspond to the posted 27.3%, but the percentage should not be mistaken for a highly precise estimate. The statistical interpretation remains descriptive and comparative, with conclusions bounded by the endpoint data and methods reported in the registry.

10. Confidence Intervals and Precision

Precision is the degree of uncertainty around an estimate. A confidence interval is one way to express that uncertainty: in general, it gives a range compatible with the data under the method used. The registry comparison calculations include intervals for risk differences, but the exact bounds are not repeated because the posted values have more than three decimal places. The interval for each genotype 3 comparison is on the negative side of zero, while the associated unadjusted p values are <0.001 and 0.076, respectively.

The group sizes affect how much information supports each percentage. The SOF 12 Weeks (GT3) result is based on 11 participants, compared with 250 participants for SOF 24 Weeks (GT3) and 73 for SOF 12 Weeks (GT2). The smaller genotype 3 12-week group means that its percentage is more sensitive to the outcome of individual participants and is less stable as an estimate of a wider population proportion. A larger group can generally yield greater precision, although precision also depends on the observed event proportion and the analysis method.

The confidence intervals relate to risk differences between groups, not to every possible source of uncertainty. They do not account for unreported design or analysis choices, and they cannot resolve the fact that the comparison groups differ in genotype. The registry record does not report confidence intervals around the individual response percentages, the confidence level used for the posted intervals, or the sponsor’s detailed analysis method. Accordingly, the interval results are best treated as unadjusted comparison estimates rather than as a complete characterization of uncertainty for the trial.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations express the number of participants per arm for each planning scenario. They are not total events. The stated calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each scenario uses a fraction of the observed effect as the effect to detect. These are planning illustrations based on the observed effect, not the trial’s original design assumptions; the original sample-size justification is not reported in the registry record.

For the comparison of SOF 12 Weeks (GT3) with SOF 12 Weeks (GT2), planning for 100% of the observed effect gives 8 participants per arm for 80% power and 10 participants per arm for 90% power. Planning for 75% of the observed effect gives 13 participants per arm for 80% power and 17 participants per arm for 90% power. Planning for 50% of the observed effect gives 25 participants per arm for 80% power and 33 participants per arm for 90% power.

For the comparison of SOF 24 Weeks (GT3) with SOF 12 Weeks (GT2), planning for 100% of the observed effect gives 239 participants per arm for 80% power and 319 participants per arm for 90% power. Planning for 75% of the observed effect gives 391 participants per arm for 80% power and 522 participants per arm for 90% power. Planning for 50% of the observed effect gives 800 participants per arm for 80% power and 1,070 participants per arm for 90% power.

In plain terms, the 80% power column describes the planned chance of detecting the specified effect under the stated assumptions if that effect is real; the 90% column uses a higher target chance and therefore requires more participants in these illustrations. Smaller effects require more participants to detect because they are harder to distinguish from random variation. These calculations are not observed power: they are prospective planning illustrations, and they do not show the probability that the completed trial found a real effect.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.932; treatment proportion p₁ = 0.273; average p̄ = 0.602.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6922 = 1.3567.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5120 = 0.4309.
4. n = (1.3567 + 0.4309)² / (-0.6588)² = 7.4, rounded up to 8 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.931506849315068                          # control proportion
p1 <- 0.272727272727273                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1682720)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 8 (80% power), 10 (90% power)
 75% of observed effect: n per arm = 13 (80% power), 17 (90% power)
 50% of observed effect: n per arm = 25 (80% power), 33 (90% power)
power.prop.test: 7.4 
Simulated power at n = 8 per arm: 0.885 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists secondary outcomes for SVR4 and SVR24, and for viral breakthrough or viral relapse. The primary endpoint is SVR12. Although the record lists four outcome measures, only two secondary outcomes are identified as posted. The results discussed for SVR12 should not be assumed to represent the full set of outcomes measured or planned.

When several outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase. In general, multiplicity methods can be used to control that issue, but no multiplicity adjustment is reported in the registry record. The comparison p values are explicitly unadjusted. The statistical analysis plan, the prespecified testing hierarchy, and whether any outcomes were designated as confirmatory or exploratory are not reported in the registry record. The number of analyses performed is also not reported in the registry record.

Missing-data methods are not described. In particular, the registry record does not report how participants without an SVR12 measurement were treated in the denominator, how missing follow-up outcomes were classified, or whether sensitivity analyses were conducted. It states that SVR12 data were not collected for the Placebo 12 Weeks (GT2/3) group, so there is no posted primary-outcome estimate for that group. This is a specific gap for interpreting the endpoint and means that the posted results do not provide a placebo-based SVR12 comparison.

The endpoint’s Full Analysis Set is defined as participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of SOF. This definition identifies an analysis population, but it does not explain the handling of every post-randomization event or missing measurement. The registry record does not report whether any additional analysis populations were used, or how the treatment-naive and treatment-experienced subgroups were represented in endpoint analyses. These omissions limit assessment of analysis choices and the robustness of the reported comparisons.

14. 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: adenocarcinoma of colon (1.2%), gastroenteritis (1.2%), arrhythmia (0.4%), haemorrhoidal haemorrhage (0.4%), biliary colic (0.4%).

The registry reports serious adverse events in 2 of 85 participants in Placebo 12 Weeks (GT2/3), 0 of 84 in SOF 12 Weeks (GT2/3), and 10 of 250 in SOF 24 Weeks (GT3). These are counts among the participants listed as at risk for serious adverse events. The figures should be read as event summaries within each group, not as adjusted comparisons or as proof that a treatment caused an event. The record lists deaths as null for these groups; death counts are not reported in the registry record.

Among other adverse events, the record reports 60 of 85 participants for Placebo 12 Weeks (GT2/3), 72 of 84 for SOF 12 Weeks (GT2/3), and 229 of 250 for SOF 24 Weeks (GT3). The registry also lists serious-event terms including adenocarcinoma of colon and gastroenteritis at 1.2% each, and arrhythmia, haemorrhoidal haemorrhage, biliary colic, and road traffic accident at 0.4% each.

These safety counts do not provide details about event timing, duration, severity beyond the serious-event category, or investigator assessment of relatedness. Such details are not reported in the registry record. Differences among these groups also need cautious interpretation because group sizes and the listed genotype and regimen categories vary.

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

The results establish what the registry reports for the SVR12 endpoint in the analyzed groups: 93.2% for SOF 12 Weeks (GT2), 27.3% for SOF 12 Weeks (GT3), and 85.2% for SOF 24 Weeks (GT3). The corresponding group sizes are 73, 11, and 250. The comparison calculations use the genotype 2 group as a reference and report unadjusted p values of <0.001 and 0.076 for the two genotype 3 groups. Together, these figures describe the observed response proportions and the registry’s posted comparisons.

They do not show a placebo-based SVR12 result, because that endpoint was not collected for the placebo group. Nor do they isolate the effect of treatment duration: the comparison groups differ in genotype, and the registry does not report subgroup-adjusted results that would separate genotype from duration. The genotype 3 12-week group contains 11 participants, so its reported proportion has limited precision compared with the larger groups.

The record does not report the original sample-size rationale, the full analysis plan, handling of missing endpoint data, or a multiplicity procedure. The posted results therefore cannot establish how sensitive the findings are to those unreported choices. The efficacy endpoint is also a defined laboratory threshold at a particular post-treatment time; it does not itself describe every aspect of participants’ clinical course or the long-term outcomes not listed in the registry.

In general, a registry result is one part of an evidence assessment, and statistical significance is not equivalent to clinical importance. These data support a bounded reading: the endpoint percentages differ across the recorded groups, but the comparisons combine different genotype and regimen categories and lack a placebo SVR12 arm. They should not be used to claim a broader treatment effect or to infer outcomes for groups not represented by the posted analysis.

16. Why This Trial Matters Statistically

This trial illustrates why a percentage needs context. The three SVR12 values are not three interchangeable estimates from one uniform group: they come from distinct genotype and treatment-duration categories, with group sizes of 73, 11, and 250. The 27.3% result is based on the smallest group, while the 85.2% result is based on the largest. Reading the percentages alongside their denominators and uncertainty helps avoid treating a small-group estimate as equally precise.

It also shows why the structure of a comparison matters. The registry uses SOF 12 Weeks (GT2) as its reference, then contrasts it with genotype 3 groups. Since genotype differs, the resulting risk differences are not pure estimates of a duration effect. This is a general lesson in clinical-trial interpretation: the statistical measure can be correctly calculated while the contrast still requires careful definition in light of the groups being compared.

The difference between the posted p value and interval for the 24-week comparison is another useful reminder that statistical summaries depend on methods. When calculation details are absent, the safest interpretation is to report the summaries without assigning an unsupported explanation. Finally, the missing placebo SVR12 result and unreported missing-data and multiplicity procedures demonstrate how registry completeness shapes what can be concluded. Statistical interpretation is not only about estimates; it also depends on the population, endpoint, comparator, and analysis details that are documented.

17. 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 trial-specific limitations affect interpretation. The placebo group has no collected SVR12 outcome, so the primary endpoint cannot be compared with placebo using the posted results. The reference group for the comparison calculations is SOF 12 Weeks (GT2), whereas the other comparison groups are genotype 3. Therefore, the contrasts combine differences in genotype with differences in regimen duration where applicable; they do not isolate duration alone.

The SOF 12 Weeks (GT3) result is based on 11 participants, limiting the precision of that percentage. The registry does not provide confidence intervals around the individual group percentages. It also does not report the original sample-size justification, detailed statistical analysis plan, missing-data handling, interim analyses, multiplicity adjustment, or separate results for treatment-naive and treatment-experienced participants.

The record contains a potential description ambiguity: the listed description for SOF 12 Weeks (GT2/3) says “Placebo to match SOF” with RBV, as does the placebo description. The registry does not clarify that wording. In addition, the official title calls the study double-blind while the masking classification says triple; the identities of the masked parties are not reported in the registry record. These details make some aspects of the intervention and masking description difficult to reconcile from the record alone.

The p value for the 24-week comparison is 0.076, while the posted recalculated confidence interval has both bounds below zero. The methods needed to explain this difference are not reported in the registry record. These limitations do not erase the reported endpoint results, but they restrict how confidently the comparisons can be interpreted.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Sofosbuvir and Ribavirin in Treatment-Naive and Treatment-Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection — NCT01682720.
• Registry record last updated 2014-10-09; status last verified 2014-10.
• Results first posted 2014-10-09.
• 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.

21. Record Summary

NCT01682720 is a completed Phase 3 randomized study of sofosbuvir (GS-7977) with ribavirin for participants with chronic genotype 2 or 3 HCV infection. The study enrolled 421 participants. The primary endpoint was SVR12, defined by HCV RNA below the lower limit of quantitation 12 weeks after the final dose.

Posted SVR12 results were 93.2% among 73 participants in SOF 12 Weeks (GT2), 27.3% among 11 in SOF 12 Weeks (GT3), and 85.2% among 250 in SOF 24 Weeks (GT3). The posted comparisons use the genotype 2 group as the reference. No placebo SVR12 result was collected. Interpretation is limited by the different genotypes in the comparisons, the small genotype 3 12-week group, and statistical and missing-data details not reported in the registry record.