Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination (FDC) With and Without Ribavirin for the Treatment of HCV: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination (FDC) With and Without Ribavirin for the Treatment of HCV (NCT01701401), a randomized phase 3 study. The primary outcome is Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12).

2. Clinical Question

3. Trial Design

The registry describes a Phase 3, multicenter, randomized, open-label, parallel-group study. The study was completed, and registry enrollment was 870. The registry lists a start date of 2012-09 and a primary completion date of 2014-03. The study evaluated safety, tolerability, and antiviral efficacy of LDV/SOF, with or without RBV, administered for 12 or 24 weeks.

The four listed groups were LDV/SOF for 12 weeks, LDV/SOF plus RBV for 12 weeks, LDV/SOF for 24 weeks, and LDV/SOF plus RBV for 24 weeks. For the primary endpoint, the posted group sizes were 214, 217, 217, and 217, respectively. These are the outcome group sizes; the registry enrollment figure is a separate record-level figure.

Random allocation can help balance measured and unmeasured participant characteristics across groups, although the registry record does not report the allocation method or whether allocation was concealed. Open-label means masking was absent. The registry record does not report additional details about treatment delivery, adherence procedures, or stratification. Those features should not be inferred from the parallel-group design.

The primary endpoint was the percentage with SVR12 in the Full Analysis Set, defined as randomized participants who received at least 1 dose of study drug. The registry also lists SVR at 4 and 24 weeks after treatment, HCV RNA measures during treatment, changes in HCV RNA, and virologic failure among the secondary outcomes. Specific posted results are available for some, but not all, of those outcomes.

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: 1015 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 were randomized 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 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 (SVR) 12 Weeks After Discontinuation of Study Drug (SVR12), measured over Posttreatment Week 12.

The primary endpoint was the percentage of participants with sustained virologic response 12 weeks after discontinuation of study drug, called SVR12. The registry definition required HCV RNA below the lower limit of quantification (LLOQ, below 25 copies/mL) 12 weeks after the last dose. The outcome is binary for each participant: the stated threshold was either met at the specified follow-up or it was not. Group results are reported as percentages.

SVR12 is used as a post-treatment measure because it assesses whether HCV RNA remains below the specified threshold after treatment has ended, rather than only measuring a response while study drug is being taken. A follow-up endpoint can therefore describe persistence of the measured virologic response over the stated interval. This is a general explanation of the endpoint's statistical role, not a claim about the clinical meaning of any individual result.

The primary endpoint was assessed in the Full Analysis Set: participants were randomized and received at least 1 dose of study drug. The registry does not report an endpoint-specific confidence interval for each posted group percentage. Comparative recalculations use the posted group counts and proportions, and should be distinguished from the sponsor's reported analyses.

7. Results Posted in the Registry

• LDV/SOF+RBV 12 Weeks: 97.2% (211/217) versus 98.6% (211/214) on control; risk difference -1.4 percentage points (95% CI -4.1 to 1.3), risk ratio 0.99 (0.96–1.01); unadjusted two-proportion z-test p = 0.322.
• LDV/SOF 24 Weeks: 98.2% (213/217) versus 98.6% (211/214) on control; risk difference -0.4 percentage points (95% CI -2.8 to 1.9), risk ratio 1.00 (0.97–1.02); unadjusted two-proportion z-test p = 0.717.
• LDV/SOF+RBV 24 Weeks: 99.1% (215/217) versus 98.6% (211/214) on control; risk difference 0.5 percentage points (95% CI -1.5 to 2.5), risk ratio 1.00 (0.98–1.03); unadjusted two-proportion z-test p = 0.642.

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 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:
  • LDV/SOF+RBV 12 Weeks: 83.4% (181/217) versus 82.2% (175/213) on control; risk difference 1.3 percentage points (95% CI -5.9 to 8.4), risk ratio 1.02 (0.93–1.11); unadjusted two-proportion z-test p = 0.731.
  • LDV/SOF 24 Weeks: 82.9% (179/216) versus 82.2% (175/213) on control; risk difference 0.7 percentage points (95% CI -6.5 to 7.9), risk ratio 1.01 (0.92–1.10); unadjusted two-proportion z-test p = 0.846.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDV/SOF+RBV 12 Weeks 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 24 Weeks 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 4

• 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:
  • LDV/SOF+RBV 12 Weeks: 99.1% (215/217) versus 100.0% (213/213) on control; risk difference -0.9 percentage points (95% CI -2.2 to 0.3), risk ratio 0.99 (0.98–1.00); unadjusted two-proportion z-test p = 0.160.
  • LDV/SOF 24 Weeks: 100.0% (216/216) versus 100.0% (213/213) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDV/SOF+RBV 12 Weeks 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 24 Weeks 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 8

• 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:
  • LDV/SOF+RBV 12 Weeks: 100.0% (215/215) versus 99.5% (212/213) on control; risk difference 0.5 percentage points (95% CI -0.4 to 1.4), risk ratio 1.00 (1.00–1.01); unadjusted two-proportion z-test p = 0.314.
  • LDV/SOF 24 Weeks: 99.5% (214/215) versus 99.5% (212/213) on control; risk difference 0.0 percentage points (95% CI -1.3 to 1.3), risk ratio 1.00 (0.99–1.01); unadjusted two-proportion z-test p = 0.995.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between LDV/SOF+RBV 12 Weeks 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 24 Weeks and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcome results available in this record cover HCV RNA below the LLOQ at Week 2, Week 4, and Week 8. Across those time points, the reported percentages are generally high, with values from 82.2% to 100.0%. This broad pattern is consistent with the high SVR12 percentages in the primary outcome in the limited sense that both describe a high frequency of the stated virologic threshold being met. Early on-treatment RNA status and post-treatment SVR12 are different endpoints, assessed at different times, and one should not be used as a substitute for the other.

The registry lists additional secondary outcomes, including SVR at 4 and 24 weeks after discontinuation, HCV RNA changes from baseline, and virologic failure. Results for those listed outcomes are not reported in the registry record in the posted secondary results represented. Their absence from the results record does not show that the outcomes were not measured.

Unadjusted secondary comparisons carry less weight than a prespecified primary analysis because multiple outcomes and contrasts create more opportunities for chance findings. If no multiplicity procedure is reported, p-values across secondary endpoints should not be treated as if each were the only test conducted. The registry record does not report a multiplicity adjustment, so the unadjusted results are best read as exploratory descriptions rather than as independent confirmatory evidence.

These results also have their own denominators, which vary by outcome and group. Differences in denominators across time points mean that the percentages do not necessarily represent the same observed participants at every assessment. The record's approach to missing secondary measurements is not reported in the registry record. The secondary pattern can contextualize the primary endpoint, but it does not resolve uncertainty in the comparative SVR12 estimates.

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 Study Drug
• Percentage of Participants With HCV RNA < LLOQ at Week 2
• Percentage of Participants With HCV RNA < LLOQ at Week 4
• Percentage of Participants With HCV RNA < LLOQ at Week 8
• Change From Baseline in HCV RNA at Week 2
• Change From Baseline in HCV RNA at Week 4
• Change From Baseline in HCV RNA at Week 8
• 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. A percentage describes the proportion meeting the definition in each group. A risk difference compares two such proportions by subtracting the comparison group's proportion from the reference group's proportion; the recalculated estimates are expressed as proportions, not as percentage-point conversions. Positive and negative signs indicate the direction of the contrast as defined for the reference and comparison groups.

What does a confidence interval describe?

A confidence interval gives a range of values compatible with the observed data under the statistical method used. It conveys uncertainty in an estimate; it is not a range containing a fixed share of individual participant outcomes, and it does not guarantee that the true effect lies within its endpoints. For these recalculated comparisons, intervals that include zero are compatible with no difference as well as with differences in either direction. The width also matters: a broader interval leaves more uncertainty about the size and direction of a contrast.

How should the p-values be read?

A p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that null hypothesis and the test assumptions were true. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. The registry's binomial tests have p < 0.001 for each group. These are group-level tests and do not directly test differences between treatment groups. The unadjusted p-values accompanying the recalculated risk differences address the contrasts with the LDV/SOF 12-week group. They are not adjusted for multiple comparisons.

These recalculations use the posted summary counts and proportions and are unadjusted. They are not a substitute for the sponsor's analysis. The registry record indicates a discrepancy, and the sponsor's own analysis takes precedence. The registry record does not report the original statistical analysis plan or enough detail to establish whether the sponsor used additional covariate adjustment, other estimands, or other procedures.

Why does the outcome rate matter for precision?

For a binary outcome, the amount of information about a proportion depends in part on the number of participants and the distribution of outcomes. When rates are close to 100%, very few participants fall outside the event category. That can make differences between high rates difficult to estimate precisely, even when the observed percentages look close. In general, a narrow range of observed outcomes can also make relative measures such as risk ratios and odds ratios sensitive to small changes in counts. This is a general statistical consideration, not an additional result from the trial.

The registry includes recalculated risk differences and, where available, relative measures. A risk difference is an absolute contrast on the proportion scale. A risk ratio compares the two proportions multiplicatively, while an odds ratio compares the odds of the outcome. These measures use different scales and can emphasize different aspects of the same data. The posted relative measures should be interpreted with their intervals and with attention to the high SVR12 rates; they should not be treated as interchangeable with the risk difference.

What is the role of randomization and masking?

Randomization is intended to support a fair comparison by assigning participants to treatment groups using a chance process. Its success depends on how allocation was carried out and how the analysis handled participants, details not fully reported in the registry record. Open-label status means participants and study personnel were not masked to group assignment. For an objectively defined laboratory endpoint, the outcome is less dependent on subjective judgment than many outcomes, but the record does not report whether laboratory assessment or other study procedures were masked.

The primary analysis population includes randomized participants who received at least 1 dose of study drug. This definition differs from an analysis of every randomized participant if anyone did not receive a dose. How missing endpoint measurements were handled is not reported in the registry record. The interpretation of a percentage therefore depends not only on the endpoint definition but also on which participants contributed an observed result and how unavailable measurements were treated.

11. Confidence Intervals and Precision

The recalculated risk-difference confidence intervals convey substantial uncertainty about the size and direction of each comparison. For LDV/SOF plus RBV over 12 weeks versus LDV/SOF over 12 weeks, the estimate was -0.014 and the interval ran from -0.041 to 0.013. For LDV/SOF over 24 weeks, the estimate was -0.004 and the interval ran from -0.028 to 0.019. For LDV/SOF plus RBV over 24 weeks, the estimate was 0.005 and the interval ran from -0.015 to 0.025. Each interval includes zero, so the recalculations do not rule out no difference.

These intervals also allow differences in either direction. They should not be interpreted as proof that groups are identical or equivalent: equivalence or noninferiority requires a prespecified margin and an analysis designed to assess that question. The registry record does not report such a margin for the primary endpoint. Nor does a nonsignificant p-value establish that a difference is absent.

The high posted SVR12 percentages leave relatively few nonresponses in each group. In general, when outcomes are this concentrated, estimates of differences can be imprecise, particularly for comparisons between groups with similar proportions. This helps explain why close observed percentages can coexist with confidence intervals that span a range of possible contrasts.

The group percentages are posted without confidence intervals. The comparison intervals are recalculated from the posted summaries, not identified as sponsor-reported intervals. Because the registry record indicates a discrepancy, the sponsor's own analysis takes precedence. The record does not report further details needed to reconcile the analyses or establish how the original sponsor analysis quantified precision for these comparisons.

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 planning figures are illustrative calculations based on the observed effect, not the trial's own design assumptions. For binary outcomes, the listed values are participants per arm. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is specified as 100%, 75%, or 50% of the observed effect. The original trial's sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if the assumed effect and analysis conditions hold. The 90% power column gives the corresponding planning count for a 90% chance. These are planning concepts, not guarantees about a future study's result. Smaller effects require more participants to distinguish them from random variation, which is why the calculations increase when the target is reduced to a smaller fraction of the observed effect.

The calculations use the observed effect as their starting point, so they are sensitive to the instability of an effect estimated from one trial. Very small observed differences can imply extremely large planning counts. Such figures should not be read as a recommendation or as evidence that the trial had a particular probability of success. They are not observed power: observed power is not an informative substitute for examining the estimate and its confidence interval.

The sample-size assumptions do not describe the study's actual allocation or original design rationale. No time-to-event planning total is relevant to these binary outcomes; the stated convention for these calculations is participants per arm.

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 = 0.986; treatment proportion p₁ = 0.972; average p̄ = 0.979.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2020 = 0.3959.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2018 = 0.1698.
4. n = (0.3959 + 0.1698)² / (-0.0136)² = 1,722.3, rounded up to 1,723 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 <- 0.985981308411215                          # control proportion
p1 <- 0.972350230414747                          # 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(1701401)
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 = 1,723 (80% power), 2,306 (90% power)
 75% of observed effect: n per arm = 2,818 (80% power), 3,771 (90% power)
 50% of observed effect: n per arm = 5,786 (80% power), 7,745 (90% power)
power.prop.test: 1722.3 
Simulated power at n = 1,723 per arm: 0.811 (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 registry reports a binomial test for each primary-outcome group, with p < 0.001 for LDV/SOF over 12 weeks, LDV/SOF plus RBV over 12 weeks, LDV/SOF over 24 weeks, and LDV/SOF plus RBV over 24 weeks. These are sponsor-reported group-level tests. They are not direct pairwise tests between the groups, and the registry record does not report comparative sponsor estimates for the contrasts described by the unadjusted recalculations.

The recalculated risk differences compare each of the other listed regimens with LDV/SOF over 12 weeks using posted summary statistics. The estimates and their intervals are descriptive unadjusted calculations. They should not be presented as if they were the sponsor's prespecified analysis. The registry record flags a discrepancy, so the sponsor's own analysis takes precedence over the recalculations.

Precedence does not make the two types of test interchangeable. A binomial test within a group asks a different question from a comparison of proportions between groups. The registry record does not report enough detail about the sponsor's analysis to explain the discrepancy or determine the exact hypothesis behind each binomial test. The record also does not report whether sponsor analyses used adjustment, a different analysis population, or other procedures. Those details are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and several secondary outcomes. The primary endpoint is SVR12. Listed secondary outcomes include SVR at 4 and 24 weeks after study drug discontinuation, HCV RNA below the LLOQ at multiple on-treatment time points, change from baseline in HCV RNA at multiple time points, and virologic failure. Examining multiple endpoints and treatment contrasts increases the chance of observing an apparently notable result by chance if each test is interpreted in isolation.

A prespecified multiplicity strategy can control how evidence is interpreted across a family of tests, for example by adjusting significance thresholds or defining a testing sequence. The registry record does not report a multiplicity adjustment or testing hierarchy. Therefore, unadjusted secondary p-values, where present, should be treated cautiously and should not be given the same confirmatory weight as a single prespecified primary comparison. The primary-outcome sponsor tests are reported as binomial tests by group, not as a clearly described family of comparative tests.

The primary population is defined as participants who were randomized and received at least 1 dose of study drug. The registry does not provide a full account of how all randomized participants were handled, whether participants were excluded after randomization, or how missing SVR12 measurements were classified. The missing-data method is not reported in the registry record. For a binary endpoint, different approaches to missing outcomes can change the estimated proportion, so the population definition and missing-data handling are important to interpretation.

Outcome-specific group sizes vary across the posted results. The registry record does not explain all denominator changes or report whether missingness differed by treatment group. The randomized, open-label design and the stated Full Analysis Set definition are known, but additional analysis-population details are not reported in the registry record.

The original statistical analysis plan, the trial's own sample-size justification, interim analyses, and any prespecified noninferiority or equivalence framework are not reported in the registry record. No conclusion about those design features should be inferred from the posted summary statistics.

16. 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: gastroenteritis (0.9%), hand fracture (0.9%), chest pain (0.5%), anaemia (0.5%), factor viii inhibition (0.5%).

The registry posts serious adverse event counts and counts for other adverse events by treatment group. For serious adverse events, the listed figures are 1 among 214 in LDV/SOF over 12 weeks, 7 among 217 in LDV/SOF plus RBV over 12 weeks, 18 among 217 in LDV/SOF over 24 weeks, and 7 among 217 in LDV/SOF plus RBV over 24 weeks. These are descriptive counts, not adjusted comparisons. The registry's other adverse event counts are 140 among 214, 168 among 217, 149 among 217, and 189 among 217 in the same group order.

The record lists gastroenteritis and hand fracture at 0.9% each among the top serious adverse event terms, and chest pain, anaemia, factor VIII inhibition, and lymphadenopathy at 0.5% each. The record does not establish that an event was caused by study treatment; adverse events occurring during a trial are not necessarily attributable to an intervention. The groups also differ in treatment duration, so raw counts alone do not account for time exposed.

Deaths are not reported in the registry record. The registry does not provide comparative safety estimates or enough detail to assess differences in event severity, timing, or exposure-adjusted rates. The serious-event figures should therefore be read as recorded counts within the listed groups, not as a complete comparative safety analysis.

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

The posted primary results show high SVR12 percentages in each listed group: 98.6% with LDV/SOF over 12 weeks, 97.2% with LDV/SOF plus RBV over 12 weeks, 98.2% with LDV/SOF over 24 weeks, and 99.1% with LDV/SOF plus RBV over 24 weeks. The record describes outcomes in treatment-naive participants with chronic genotype 1 HCV infection. These findings do not automatically generalize to populations or treatment settings not described in the registry record.

The recalculated unadjusted risk differences are small in magnitude on the proportion scale, and their confidence intervals include zero. This means the recalculations do not establish a difference between each listed regimen and the LDV/SOF 12-week comparison group. It also does not prove that the regimens are identical or equivalent. A claim of equivalence or noninferiority would require an appropriate prespecified framework, which is not reported in the registry record.

The sponsor-reported binomial tests with p < 0.001 are tests within individual groups and should not be interpreted as pairwise evidence that one group outperforms another. The registry indicates a discrepancy between sponsor analysis and recalculation, so the sponsor's own analysis takes precedence. The record does not provide enough detail to reconcile that difference fully.

The posted primary endpoint measures HCV RNA below the LLOQ at a defined time after treatment, not every aspect of health, quality of life, adverse effects, or long-term outcomes. The safety counts are descriptive and do not establish causation. Results should be interpreted with the registry's limits on reported methods, missing-data handling, and multiplicity in mind.

These statistics characterize the posted trial record; they are not medical advice and do not determine which regimen is appropriate for an individual. The registry record alone cannot support conclusions beyond its population, endpoint definitions, follow-up measures, and reported analyses.

18. Why This Trial Matters Statistically

This trial raises several useful statistical issues in a setting where the primary outcome percentages are close to the upper end of the scale. When nearly all observed participants meet a binary endpoint, differences between groups can be difficult to estimate precisely. A high percentage in each group is not the same as precise evidence that the groups have the same underlying outcome rate.

The study also illustrates why the question answered by a test matters. A binomial test conducted separately within each group is not a comparison of groups. Direct comparative estimates, such as risk differences, address a different question and should be considered alongside their uncertainty. Here the registry reports group-level binomial p-values, while the unadjusted recalculations provide contrasts against the LDV/SOF 12-week group. The registry flags a discrepancy, making the distinction between sponsor results and recalculation important.

Randomization supports comparisons, while the open-label design and incomplete reporting of analysis details limit what can be inferred from registry summaries alone. The Full Analysis Set is defined, but the missing-data approach, multiplicity strategy, and original sample-size rationale are not reported. These omissions demonstrate why effect estimates should be read in the context of prespecified methods, analysis populations, and the handling of multiple outcomes.

Finally, planning calculations based on an observed effect are not a retrospective measure of whether a trial was adequately powered. They depend on assumptions and can produce very large participant requirements when the observed contrast is small. Interpreting the estimate and its confidence interval is more informative than treating a planning illustration or an isolated p-value as a complete summary of evidence.

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.

The registry record does not report the original statistical analysis plan, original sample-size justification, interim analyses, allocation concealment details, or multiplicity strategy. It also does not report the missing-data approach for the primary or secondary endpoints. These gaps limit assessment of whether the posted analyses followed prespecified procedures and how unavailable outcomes affected the estimates.

The primary-outcome group percentages are presented without group-specific confidence intervals. The comparative intervals are unadjusted recalculations rather than sponsor-reported comparative intervals. Because the registry record indicates a discrepancy, the sponsor's own analysis takes precedence, but the details needed to reconcile the difference are not reported in the registry record.

Open-label assignment means masking was absent. The primary endpoint is defined using a laboratory threshold, but the registry record does not report whether laboratory assessment or other outcome procedures were masked. The group results are also based on an analysis set defined as randomized participants who received at least 1 dose, and further detail about participant disposition and missing measurements is not reported.

The trial population was treatment-naive participants with chronic genotype 1 HCV infection. The record does not support automatic generalization to other populations. Secondary outcomes are listed, but results are posted for only some of those outcomes in the available record. The reported adverse event counts are descriptive; deaths are not reported in the registry record, and exposure-adjusted safety comparisons are not presented.

These are limitations of the registry record and the available summary statistics. They do not establish that the unreported procedures were absent; their details are simply not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination (FDC) With and Without Ribavirin for the Treatment of HCV — NCT01701401.
• Registry record last updated 2018-11-16; status last verified 2015-03.
• Results first posted 2015-03-27.
• 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

NCT01701401 is a completed Phase 3, multicenter, randomized, open-label, parallel-group study of LDV/SOF with or without RBV for 12 or 24 weeks in treatment-naive participants with chronic genotype 1 HCV infection. Registry enrollment was 870. The primary outcome was SVR12, defined as HCV RNA below the LLOQ 12 weeks after the last study-drug dose, in the Full Analysis Set.

Posted SVR12 percentages ranged from 97.2% to 99.1% across the listed groups. The unadjusted recalculated risk-difference intervals include zero, but the registry indicates a discrepancy, so the sponsor's own analysis takes precedence. Sponsor-reported binomial tests are group-level tests rather than direct pairwise comparisons. Important details about multiplicity, missing data, and the original sample-size rationale are not reported in the registry record.