Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Participants With Chronic Genotype 2 HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Participants With Chronic Genotype 2 HCV Infection (NCT02738333), a randomized phase 3 study. The primary outcome is Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12).

2. Clinical Question

The study’s stated objectives were to evaluate antiviral efficacy of ledipasvir/sofosbuvir and to evaluate the safety and tolerability of that combination and sofosbuvir plus ribavirin in chronic genotype 2 infection. The randomized comparison relevant to the primary result is between the Cohort 1 groups. Cohort 2 provides an outcome estimate for participants described as ineligible for or intolerant to ribavirin; it should not be read as another randomized treatment comparison unless further design details establish that.

The result addresses virologic response at a defined post-treatment time point. It does not, by itself, answer questions about longer-term clinical outcomes, comparative effects in populations not represented in the record, or the reasons individual participants did or did not achieve the endpoint. The registry record does not report a broader clinical outcome as the primary endpoint.

3. Trial Design

This was a phase 3b, multicenter, randomized, open-label, parallel study. The registry record lists enrollment of 239 and identifies chronic hepatitis C virus infection as the condition. The study status is completed. The recorded start date is 2016-04-12 and the primary completion date is 2017-02-14.

The listed treatment groups were ledipasvir/sofosbuvir (LDV/SOF) in Cohort 1, sofosbuvir plus ribavirin (SOF+RBV) in Cohort 1, and LDV/SOF in Cohort 2. Both Cohort 1 regimens were given for 12 weeks. Cohort 2 was described as including participants ineligible for or intolerant to ribavirin therapy, who received LDV/SOF for 12 weeks. That description distinguishes the Cohort 2 population from the Cohort 1 randomized comparison; the registry record does not give additional detail on how Cohort 2 was formed.

Open-label means the study was recorded as having no masking. The record does not report details about who knew treatment assignments or whether outcome assessment involved any additional safeguards. The primary analysis population is described as participants who were randomized and took at least 1 dose of study drug. For the primary outcome, the posted group denominators are 106 for LDV/SOF Cohort 1, 108 for SOF+RBV Cohort 1, and 25 for LDV/SOF Cohort 2.

The sponsor is Gilead Sciences. The record does not report the original sample-size justification, randomization procedure, allocation ratio, detailed conduct of follow-up, or the trial’s full statistical analysis plan. Those items should not be inferred from the design labels or from the posted outcome estimates.

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: 266 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: participants who were randomized and took 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 took at least 1 dose of study drug

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 is the percentage of participants with sustained virologic response 12 weeks after discontinuation of therapy, abbreviated SVR12. A participant met the endpoint when HCV RNA was below the lower limit of quantitation, defined in the record as 15 IU/mL, at 12 weeks after stopping study treatment. The stated timeframe is posttreatment Week 12.

This is a binary outcome at the participant level: each participant either meets the endpoint definition or does not. Reporting the percentage gives the proportion of the analysis group that met the virologic threshold. The endpoint is used to describe whether viral RNA remains below the specified measurement limit at a defined time after treatment has ended. The timing matters: the measure is not an on-treatment viral-load reading, nor does it describe the result at the end of the 12-week treatment period.

The primary analysis population was the Full Analysis Set, defined in the registry record as randomized participants who took at least 1 dose of study drug. The record presents a percentage and a 95% confidence interval for each group. Those intervals convey uncertainty around the group-level estimates; they do not show the range of individual participants’ responses. The endpoint is a virologic outcome, and the registry record does not identify it as a measure of symptoms, liver function, or other clinical outcomes.

SVR12 is the primary endpoint specified in the record. Secondary outcomes include SVR at other post-treatment times and HCV RNA measurements during treatment, but they are not interchangeable with the primary post-treatment endpoint.

7. Results Posted in the Registry

• SOF+RBV (Cohort 1): 95.4% (103/108) versus 96.2% (102/106) on control; risk difference -0.9 percentage points (95% CI -6.2 to 4.5), risk ratio 0.99 (0.94–1.05); unadjusted two-proportion z-test p = 0.755.
• LDV/SOF (Cohort 2): 96.0% (24/25) versus 96.2% (102/106) on control; risk difference -0.2 percentage points (95% CI -8.7 to 8.3), risk ratio 1.00 (0.91–1.09); unadjusted two-proportion z-test p = 0.958.

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 HCV RNA < LLOQ at Week 1

• 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+RBV (Cohort 1): 31.5% (34/108) versus 24.5% (26/106) on control; risk difference 7.0 percentage points (95% CI -5.0 to 18.9), risk ratio 1.28 (0.83–1.98); unadjusted two-proportion z-test p = 0.258.
  • LDV/SOF (Cohort 2): 32.0% (8/25) versus 24.5% (26/106) on control; risk difference 7.5 percentage points (95% CI -12.6 to 27.5), risk ratio 1.30 (0.67–2.53); unadjusted two-proportion z-test p = 0.443.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SOF+RBV (Cohort 1) 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 LDV/SOF (Cohort 2) and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With HCV RNA < LLOQ at Week 2

• 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+RBV (Cohort 1): 76.6% (82/107) versus 73.6% (78/106) on control; risk difference 3.1 percentage points (95% CI -8.6 to 14.7), risk ratio 1.04 (0.89–1.22); unadjusted two-proportion z-test p = 0.607.
  • LDV/SOF (Cohort 2): 76.0% (19/25) versus 73.6% (78/106) on control; risk difference 2.4 percentage points (95% CI -16.3 to 21.1), risk ratio 1.03 (0.81–1.32); unadjusted two-proportion z-test p = 0.804.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SOF+RBV (Cohort 1) 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 LDV/SOF (Cohort 2) and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With HCV RNA < LLOQ at Week 3

• 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+RBV (Cohort 1): 90.7% (97/107) versus 90.6% (96/106) on control; risk difference 0.1 percentage points (95% CI -7.7 to 7.9), risk ratio 1.00 (0.92–1.09); unadjusted two-proportion z-test p = 0.982.
  • LDV/SOF (Cohort 2): 96.0% (24/25) versus 90.6% (96/106) on control; risk difference 5.4 percentage points (95% CI -4.1 to 14.9), risk ratio 1.06 (0.96–1.17); unadjusted two-proportion z-test p = 0.378.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SOF+RBV (Cohort 1) 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 LDV/SOF (Cohort 2) and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes include SVR at post-treatment time points and HCV RNA below the lower limit of quantitation at several treatment weeks. The available posted estimates for the early on-treatment RNA outcomes show increasing percentages across the reported Week 1, Week 2, and Week 3 time points in the three groups. By Week 3, the reported percentages are generally high. These are descriptive patterns in the posted outcomes, not a substitute for the primary post-treatment SVR12 endpoint.

The Week 1 to Week 3 estimates have confidence intervals, and the recalculated pairwise contrasts are unadjusted. They do not establish that one treatment produces a reliably different early viral response. The direction and apparent size of a contrast can vary across time points, and the uncertainty intervals are relevant to interpreting each estimate. No claim about the remaining secondary endpoints should be made from these early-week summaries; their results are not reported in the registry record details used for this interpretation.

Secondary outcomes are useful for describing response over time and for adding context to the primary result. However, testing many outcomes or time points creates a multiplicity concern: the chance of obtaining apparently notable results by chance can increase when many comparisons are considered. Whether and how the trial addressed multiplicity is not reported in the registry record. Therefore, unadjusted secondary results carry less weight as confirmatory evidence than the prespecified primary endpoint and the sponsor’s specified primary analysis.

The early on-treatment RNA measures and SVR12 are related virologic measures but have different definitions and timeframes. A response during treatment does not itself establish the post-treatment endpoint. The secondary results should be interpreted as supporting descriptive information, with attention to their intervals and the absence of reported multiplicity procedures.

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

• Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4)
• Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24)
• Percentage of Participants With HCV RNA < LLOQ at Week 1
• Percentage of Participants With HCV RNA < LLOQ at Week 2
• Percentage of Participants With HCV RNA < LLOQ at Week 3
• Percentage of Participants With HCV RNA < LLOQ at Week 4
• Percentage of Participants With HCV RNA < LLOQ at Week 5
• Percentage of Participants With HCV RNA < LLOQ at Week 6

9. Statistical Interpretation

10. Statistical Methods Explained

Several statistical ideas help distinguish the observed percentages from the comparative claims that can be made from them. The registry record reports a binary endpoint, confidence intervals, and a sponsor analysis labelled non-inferiority. The additional comparative estimates are unadjusted recalculations from posted group summaries. Each type of result answers a different question.

What does a percentage describe?

For a binary outcome, the percentage is the observed proportion of participants meeting the endpoint definition. Here, the event is SVR12: HCV RNA below the lower limit of quantitation at posttreatment Week 12. The outcome percentages are calculated within each reported group. A percentage does not convey how uncertain the estimate is; that is why the registry record also reports confidence intervals.

What does a confidence interval mean?

A confidence interval is a range of values compatible with the observed data under the statistical method used. It communicates uncertainty in an estimated group percentage or treatment contrast. A wider interval means the estimate is less precise, while a narrower interval indicates greater precision under the method’s assumptions. A confidence interval is not a range containing a stated proportion of individual participant outcomes, and it does not make every value in the range equally likely.

What does a risk difference express?

A risk difference compares two event proportions by subtracting one group’s proportion from the other. A value of zero corresponds to equal observed proportions; values on either side represent differences in opposite directions according to the stated group order. The recalculated risk differences use the posted summary counts and an unadjusted comparison. Their confidence intervals quantify uncertainty in those contrasts. They do not incorporate an adjustment unless one is explicitly described.

The recalculated risk difference for SOF+RBV versus LDV/SOF Cohort 1 is -0.009, with a 95% confidence interval from -0.062 to 0.045. The recalculated contrast for LDV/SOF Cohort 2 versus LDV/SOF Cohort 1 is -0.002, with a 95% confidence interval from -0.087 to 0.083. The Cohort 2 estimate is particularly imprecise. These recalculations are descriptive comparisons and should not be substituted for any sponsor analysis with a different objective or method.

How is non-inferiority different from testing for a difference?

A non-inferiority analysis asks whether an intervention is not worse than a comparator by more than a prespecified margin. It is not the same as showing that two treatments are equivalent, and it is not the same as finding no statistically significant difference. The registry record labels the Cohort 1 analysis non-inferiority and reports a difference in proportions of 0.9 with a 95% confidence interval from -5.3 to 7.1. The non-inferiority margin and detailed analysis method are not reported in the registry record, so the criterion used for that conclusion cannot be checked from these registry entries alone.

Why can a small study have wide intervals?

Estimates are less precise when there is limited information in a group. The posted Cohort 2 group is smaller than either Cohort 1 group, and its SVR12 interval is wider. This is a general statistical relationship: fewer observations generally leave more uncertainty about a proportion, particularly when the observed proportion is near an endpoint of its possible range. The interval should therefore be read together with the estimate, rather than focusing on the estimate alone.

Statistical significance and clinical importance are separate concepts. An interval that includes zero in a treatment contrast does not show that the treatments are identical; it indicates that the data and method do not rule out zero difference at the interval’s stated confidence level. Determining whether a range of effects is clinically acceptable requires a justified clinical threshold, which is not reported in the registry record.

The registry record does not report the complete statistical analysis plan, detailed handling of missing endpoint data, or all model specifications. Thus the unadjusted recalculations are best understood as checks based on the posted summary statistics, not as reconstructions of the sponsor’s full analysis.

11. Confidence Intervals and Precision

For SVR12, the Cohort 1 estimate for LDV/SOF is 96.2%, with a 95% confidence interval of 90.6% to 99.0%. The estimate for SOF+RBV is 95.4%, with an interval of 89.5% to 98.5%. These intervals overlap. The posted estimates are close, but overlap alone is not a formal test of non-inferiority, equivalence, or equality.

The recalculated Cohort 1 risk difference is -0.009, with an interval from -0.062 to 0.045. Because this interval includes zero, the unadjusted comparison is compatible with no difference as well as with differences in either direction within the interval. Its width matters: the data do not pin down the contrast to a narrow range. The reported sponsor non-inferiority interval is expressed as 0.9, from -5.3 to 7.1, and should be considered with the non-inferiority margin; that margin is not reported in the registry record.

The LDV/SOF Cohort 2 SVR12 estimate is 96.0%, but its 95% confidence interval, 79.6% to 99.9%, is considerably wider. This reflects less precision in that group’s estimate and means a broad range of underlying response proportions remains compatible with the result. It is important not to treat a high point estimate as equally precise across groups.

In general, a confidence interval describes uncertainty under the method used; it is not a guarantee about the true value. The posted intervals address uncertainty in outcome estimates and contrasts, not uncertainty about whether the study population represents other populations or whether the analysis plan was appropriate. The registry record does not report enough detail to assess every source of uncertainty.

12. 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 use a planning calculation based on the observed effect, not the trial’s original design. For these binary outcomes, the figures are participants per arm. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s own sample-size assumptions are not reported in the registry record.

The 80% power column describes an illustrative number of participants per arm for a design that would have an 80% chance of detecting the specified effect under the stated assumptions, if that effect and assumptions were correct. The 90% power column gives the corresponding planning target for a higher chance of detection. These are design illustrations, not a description of the number of participants enrolled in this trial.

The rows that use 100%, 75%, and 50% of the observed effect illustrate progressively smaller effects to detect. Smaller effects generally require more participants because they are harder to distinguish from random variation. That pattern is visible in the planning figures, including the very large illustrations for some outcomes where the observed group contrast was small. Such figures depend strongly on the observed effect and should not be treated as a reliable forecast of what a future study will need.

This is not observed power. It is a planning calculation based on the observed contrast and stated assumptions, and it does not establish whether the completed study was adequately designed. The sample-size curve should be read in the same way: it illustrates how planning requirements change as the assumed effect changes, rather than displaying a property measured from the completed trial.

13. 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 = 0.962; treatment proportion p₁ = 0.954; average p̄ = 0.958.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2837 = 0.5561.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2837 = 0.2387.
4. n = (0.5561 + 0.2387)² / (-0.0086)² = 8,621.0, rounded up to 8,622 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 <- 0.962264150943396                          # control proportion
p1 <- 0.953703703703704                          # 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(2738333)
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 = 8,622 (80% power), 11,541 (90% power)
 75% of observed effect: n per arm = 14,954 (80% power), 20,018 (90% power)
 50% of observed effect: n per arm = 32,805 (80% power), 43,915 (90% power)
power.prop.test: 8621 
Simulated power at n = 8,622 per arm: 0.802 (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.

14. Analyses Reported by the Sponsor

The sponsor’s posted Cohort 1 analysis is labelled non-inferiority and reports a difference in proportions of 0.9, with a 95% confidence interval from -5.3 to 7.1. No p-value or analysis method is reported for that result, and the non-inferiority margin is not reported in the registry record. The interval therefore cannot be evaluated against the study’s decision threshold from the registry entries alone.

The unadjusted recalculation from the posted summary statistics gives a risk difference of -0.009 for SOF+RBV relative to LDV/SOF Cohort 1, with a 95% confidence interval from -0.062 to 0.045. It is a simple comparison calculated from the posted counts and is not the same as the sponsor’s non-inferiority analysis. The registry record does not provide enough detail to determine why the numerical scales or estimates differ, so no cause should be assigned.

The record does not flag a discrepancy between the posted results and the recalculation. Even so, the distinction in purpose remains important: the sponsor’s analysis is the reported non-inferiority result, while the recalculation describes an unadjusted contrast. Neither result should be used to claim equivalence without the relevant margin and analysis details. The sponsor analysis does not include enough reported information to reconstruct its procedure independently.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study assesses multiple endpoints, time points, or treatment comparisons. Even if each individual test uses a conventional threshold, repeatedly testing hypotheses can increase the chance of at least one apparently positive result arising by chance. This is a general statistical issue, not evidence that any particular result in this study is false.

The registry record lists 23 outcome measures and identifies secondary outcomes that include SVR4, SVR24, and HCV RNA below the lower limit of quantitation at multiple treatment weeks. It reports 21 posted secondary outcomes, but the detailed results available for interpretation include only some of them. The registry record does not report whether a multiplicity adjustment, hierarchical testing procedure, or other prespecified approach was used. Unadjusted results across multiple secondary outcomes should therefore be treated as exploratory or descriptive unless the trial’s analysis plan supplies further context.

The analysis population for the primary endpoint is defined as randomized participants who took at least 1 dose of study drug. The registry record does not report detailed counts or reasons for missing primary endpoint assessments, the method used to handle missing results, or whether any sensitivity analyses were performed. Those omissions limit assessment of the potential impact of missing data. The Full Analysis Set definition is useful, but it does not by itself explain how participants without an observed endpoint measurement were handled.

The record reports the primary outcome as percentages with 95% confidence intervals and includes a sponsor analysis labelled non-inferiority. It does not report the complete statistical analysis plan, the non-inferiority margin, detailed modeling choices, or any interim analysis procedures. The absence of these details in the registry record is not evidence that the procedures were absent; it means they cannot be assessed from the reported information.

These limitations matter when interpreting the certainty and confirmatory status of findings. The primary result is the central endpoint, while secondary analyses and unadjusted recalculations should be considered in light of the unavailable multiplicity and missing-data details.

16. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cerebral infarction (4.0%), mallory-weiss syndrome (0.9%), hip fracture (0.9%).

The registry record lists one serious adverse event in each of the three groups: LDV/SOF Cohort 1, SOF+RBV Cohort 1, and LDV/SOF Cohort 2. It records one death in LDV/SOF Cohort 1 and none in the other two groups. These are counts reported for the groups, not estimates of a causal treatment effect. The record does not state that the death was caused by study treatment.

For other adverse events, the record lists 25 affected participants in LDV/SOF Cohort 1, 48 in SOF+RBV Cohort 1, and 7 in LDV/SOF Cohort 2. These counts should be read alongside their respective group denominators and the study’s adverse-event definitions, which are not fully detailed in the registry entries. Counts alone do not describe severity, duration, or whether events were considered treatment-related.

The listed top serious adverse event terms include cerebral infarction at 4.0%, Mallory-Weiss syndrome at 0.9%, and hip fracture at 0.9%. The registry record does not provide enough context to reconcile those term percentages with the group-level serious event counts, so they should not be combined or interpreted as rates attributable to a particular treatment. Safety comparisons also require consideration of follow-up and event ascertainment, details not reported in the registry record.

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

The primary result describes the proportion of participants in each reported group who met the registry’s SVR12 definition: HCV RNA below the lower limit of quantitation at 12 weeks after treatment stopped. The posted Cohort 1 percentages were 96.2% for LDV/SOF and 95.4% for SOF+RBV. The LDV/SOF Cohort 2 percentage was 96.0%, with a wider confidence interval than the Cohort 1 estimates.

These results support a descriptive statement that high observed SVR12 percentages were recorded in the studied groups. They do not show that the regimens are identical, establish equivalence, or by themselves demonstrate the sponsor’s non-inferiority criterion. The sponsor analysis is labelled non-inferiority, but the margin needed to assess that claim is not reported in the registry record. The unadjusted recalculation is not a substitute for that analysis.

The results also do not establish how the regimens would compare in populations outside those studied. Cohort 2 was described as involving participants ineligible for or intolerant to ribavirin and was much smaller than the Cohort 1 groups. Its estimate is informative as a group description but should not be treated as a randomized comparison with the other groups. The record does not report enough detail to assess all aspects of participant selection or generalizability.

SVR12 is a virologic endpoint at a defined time after treatment. It does not directly measure symptoms, quality of life, liver outcomes, or other clinical consequences. Nor do these efficacy results settle safety questions: the adverse-event counts are descriptive and do not establish that events were caused by treatment. The findings should be read as estimates with uncertainty, within the enrolled study population and the available registry reporting.

18. Why This Trial Matters Statistically

This study illustrates why statistical interpretation depends on the study question and the type of comparison, not just on the size of the observed percentages. The primary outcome percentages are close in the two Cohort 1 groups, but a non-inferiority claim requires a prespecified margin and a suitable analysis. The registry record reports the sponsor’s non-inferiority result but does not report the margin, limiting independent assessment of that claim.

The trial also separates a randomized comparison from a cohort described by eligibility for ribavirin. Treating all three groups as if they formed a single randomized comparison would overlook that distinction. The Cohort 2 estimate has a wider confidence interval, underscoring how group size and precision affect the strength of conclusions.

Finally, the record demonstrates the value of separating endpoint estimates, interval uncertainty, sponsor analyses, and recalculated comparisons. A high percentage is not a complete statistical conclusion; uncertainty, analysis objective, population, and missing details all matter. The secondary outcomes broaden the descriptive picture, while multiplicity and unreported analysis details limit how strongly they can be interpreted.

19. 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. First, the registry record does not report the non-inferiority margin for the Cohort 1 analysis. Although the sponsor analysis is labelled non-inferiority, the margin is necessary to judge whether the reported interval meets the intended criterion. The analysis method and sponsor p-value are also not reported.

Second, Cohort 2 is described as including participants ineligible for or intolerant to ribavirin, and its posted outcome group is smaller than the two Cohort 1 groups. Its estimate therefore has a wider confidence interval and should be read descriptively rather than as a randomized contrast against Cohort 1. The record does not give further details about how this cohort was assembled.

Third, the record does not report detailed handling of missing primary endpoint data, reasons for missing assessments, sensitivity analyses, or the complete statistical analysis plan. It also does not report whether multiplicity was addressed across the numerous outcome measures and time points. These omissions constrain independent review of the analyses.

Finally, the study was open-label, with no masking recorded. The endpoint is a laboratory-defined virologic measure, but the registry record does not provide details about outcome assessment procedures. Adverse-event information is presented as counts and selected terms, without enough detail to establish causality, severity patterns, or comparative safety effects. These limitations do not negate the posted results, but they narrow the conclusions that can be drawn from the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Participants With Chronic Genotype 2 HCV Infection — NCT02738333.
• Registry record last updated 2018-11-16; status last verified 2018-02.
• Results first posted 2018-03-14.
• 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.

23. Record Summary

NCT02738333 was a completed, phase 3b, multicenter, randomized, open-label, parallel study of treatment for chronic genotype 2 hepatitis C virus infection. The primary endpoint was SVR12: HCV RNA below the lower limit of quantitation, defined as 15 IU/mL, at posttreatment Week 12.

The Cohort 1 SVR12 estimates were 96.2% for LDV/SOF and 95.4% for SOF+RBV. The sponsor reported a non-inferiority analysis, but the margin is not reported in the registry record. LDV/SOF Cohort 2, described as participants ineligible for or intolerant to ribavirin, had an SVR12 estimate of 96.0% and a wider confidence interval. The findings should be interpreted as group estimates with uncertainty, not as proof of equivalence or as a complete assessment of clinical outcomes or safety.