SMV + SOF With/Without RBV for IFN-II Patients With CHC: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for SMV + SOF With/Without RBV for IFN-II Patients With CHC (NCT02214420), a randomized phase 4 study. The primary outcome is Sustained Viral Response.

2. Clinical Question

The registry record describes a comparison in patients with chronic hepatitis C who were interferon-intolerant or ineligible. Its rationale discusses the challenges of pegylated interferon-based regimens, including severe side effects and other conditions that may make those regimens unsuitable. The trial compared two oral treatment regimens, each planned for 12 weeks, and assessed whether hepatitis C virus RNA was undetectable 12 weeks after treatment ended.

The posted counts are 13 of 14 participants in the SMV+SOF arm and 8 of 10 in the SMV+SOF+RBV arm. The registry’s comparison summary estimates a risk difference of -0.129 for the ribavirin arm relative to the SMV+SOF arm. That estimate is accompanied by a confidence interval that spans both negative and positive values, so the observed arm difference is imprecisely estimated. The comparison describes the trial results; it does not by itself establish that either regimen is superior, equivalent, or appropriate for an individual patient.

3. Trial Design

This was a Phase 4, randomized, parallel-arm trial with no masking. The registry record lists 24 participants enrolled and a completed status. The trial start is recorded as 2014-10 and primary completion as 2016-06. The sponsor is SC Liver Research Consortium, LLC.

One arm received simeprevir plus sofosbuvir, and the other received the same two drugs plus ribavirin. Both regimens were planned for 12 weeks. The arm descriptions specify simeprevir 150mg once daily and sofosbuvir 400mg once daily; the combination arm also received weight-based ribavirin at 1000-1200 mg/day. The record identifies the two arms as SMV+SOF and SMV+SOF+RBV.

Randomization means assignment was intended to allocate participants to treatment arms by chance, but the method used to generate the assignment sequence, conceal allocation, or handle departures from assigned treatment is not reported in the registry record. The trial was unmasked: participants and trial personnel were not described as blinded. Further details about the setting, number of sites, eligibility criteria beyond the stated population, baseline characteristics, follow-up procedures, and treatment adherence are not reported in the registry record.

The primary outcome was sustained virologic response measured 12 weeks after treatment. It is a binary participant outcome: each participant either met the stated SVR12 definition or did not. The registry lists no secondary outcomes. The arm counts are 13 participants with SVR12 among 14 in SMV+SOF and 8 among 10 in SMV+SOF+RBV. The registry record does not describe a formal sample-size justification or its original planning assumptions.

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.

Overall Study

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.

6. Primary Endpoint

The registry lists the primary outcome as Sustained Viral Response, measured over 12 weeks.

The primary endpoint is sustained virologic response 12 weeks after treatment, or SVR12. The registry defines it as undetectable hepatitis C virus ribonucleic acid (HCV RNA) 12 weeks after treatment ends. The outcome is recorded as a count of participants, making it a binary endpoint at the participant level: the result is classified according to whether each participant satisfies the stated definition.

SVR12 is used as a virologic outcome because it records whether HCV RNA is detectable at a specified follow-up point after therapy. The registry states that achieving SVR12 is generally indicative of hepatitis C infection being cured. That description explains the endpoint’s clinical relevance; the endpoint itself is the RNA result at the defined follow-up time, not a broader assessment of every aspect of health or later outcomes.

Both arms were assigned a 12-week treatment course, and the endpoint was assessed 12 weeks after treatment. These are distinct time periods: the endpoint follow-up occurs after the treatment period ends. The posted results report 13 participants with SVR12 among 14 assigned to SMV+SOF and 8 among 10 assigned to SMV+SOF+RBV. The registry does not report how participants with unavailable follow-up measurements were handled, whether any endpoint classifications were confirmed by a particular laboratory process, or whether the assessment was performed without knowledge of arm assignment.

7. Results Posted in the Registry

• SMV+SOF+RBV: 80.0% (8/10) versus 92.9% (13/14) on control; risk difference -12.9 percentage points (95% CI -41.1 to 15.4), risk ratio 0.86 (0.61–1.21); unadjusted two-proportion z-test p = 0.348.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary and reported as a count of participants meeting the SVR12 definition. For a binary endpoint, each participant contributes an outcome classification, and the arm-level summaries can be compared using absolute and relative measures. The registry’s comparison summary includes a risk difference, a risk ratio, and an odds ratio. It also reports an unadjusted p-value and confidence intervals for the effect estimates. The specific methods used to calculate those intervals and the p-value are not reported in the registry record.

In general, a risk difference compares the outcome proportions between two groups by subtracting one proportion from the other. It is measured on the probability scale, so zero represents no difference between groups. The reported risk difference is -0.129 for SMV+SOF+RBV relative to SMV+SOF. The negative sign indicates that the estimated response proportion was lower in the arm receiving ribavirin. Its confidence interval, -0.411 to 0.154, extends across zero, so the data are compatible with effects in either direction as well as no difference.

In general, a risk ratio compares the probability of the outcome in one group with the probability in another. A value of 1 represents equal probabilities; values below or above 1 indicate a lower or higher probability in the numerator group, respectively. The posted risk ratio is 0.862, with a confidence interval from 0.612 to 1.213. The interval includes 1, which is the no-association value for a ratio measure.

In general, an odds ratio compares the odds of an outcome between groups rather than comparing probabilities directly. A value of 1 represents equal odds. The reported odds ratio is 0.308, with a confidence interval from 0.024 to 3.968. This interval is broad and includes 1. An odds ratio is not the same quantity as a risk ratio, especially when outcomes are common; the two measures should not be interchanged as if they had identical interpretations.

The unadjusted p-value is 0.348. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, nor does it measure the probability that the result will replicate. The registry does not report the precise test used or whether any adjusted inferential analysis was conducted. The reported p-value is explicitly unadjusted.

In general, confidence intervals express statistical uncertainty around an estimate under a specified method and its assumptions. They do not capture every source of uncertainty: for example, they do not automatically account for missing outcomes, measurement problems, selection into the trial, or differences between the trial population and other populations. Interpretation therefore depends on both the numerical interval and the quality and completeness of the underlying study data.

Randomized allocation is intended to reduce systematic differences between treatment groups at assignment. The record identifies the trial as randomized, but does not describe sequence generation, allocation concealment, stratification, or the analysis population. It is therefore not possible to determine from the registry whether the posted comparison followed an intention-to-treat approach, a per-protocol approach, or another prespecified population definition.

The outcome is a count, and the comparison concerns the number meeting the endpoint relative to the number in each arm. The registry posts 13 of 14 for SMV+SOF and 8 of 10 for SMV+SOF+RBV. It does not describe the handling of participants who discontinued treatment, had an unavailable RNA measurement, or otherwise lacked an endpoint classification. No assumptions about such participants should be inferred from the observed counts alone.

In general, prespecification matters because choices about endpoints, time points, statistical tests, and analysis populations can affect interpretation. The registry lists one primary outcome measure and no secondary outcomes, but does not report a full statistical analysis plan. Details such as model adjustment, subgroup analyses, interim analyses, or any multiplicity procedure are not reported in the registry record. The posted result is therefore best interpreted using the outcome definition and estimates that are recorded, without assuming additional analysis decisions.

10. Confidence Intervals and Precision

The main absolute-effect estimate is a risk difference of -0.129 for SMV+SOF+RBV relative to SMV+SOF. Its confidence interval runs from -0.411 to 0.154. Because the interval crosses zero, the observed data are compatible with no arm difference and with differences favoring either arm. The interval is wide relative to the point estimate, so the direction and magnitude of the underlying difference remain uncertain.

The other reported effect measures also have broad intervals: the risk ratio is 0.862, with a confidence interval from 0.612 to 1.213, and the odds ratio is 0.308, with a confidence interval from 0.024 to 3.968. The risk-ratio interval includes 1, as does the odds-ratio interval. For ratio measures, 1 is the value corresponding to no difference. The different measures present the same comparison on different scales, and their uncertainty should be considered rather than focusing only on their point estimates.

In general, a confidence interval is a measure of sampling uncertainty under the method used to calculate it. It is not a guarantee that the true effect lies within the interval, nor does it account automatically for unreported missing-data decisions, bias, or limitations in generalizability. The calculation method for these intervals is not reported in the registry record.

The small arm counts are important context for precision: 14 participants were in SMV+SOF and 10 were in SMV+SOF+RBV. With few participants, the estimate can be sensitive to the outcome of individual participants, and the confidence intervals can remain broad even when the observed arm counts appear different. The registry’s unadjusted p-value is 0.348; it should be considered alongside the effect estimate and its interval, not used as a substitute for them.

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 planning figures are participants per arm, not total events. They are an illustration based on the observed effect, rather than a report of the trial’s original design calculations. The assumptions listed for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect.

The 80% power column gives the illustrative number of participants per arm for an analysis to have an 80% chance of detecting the assumed effect under those planning assumptions, if that effect were the true effect and the assumptions held. The 90% power column gives the corresponding planning number for a 90% chance. These percentages describe the design calculations, not the probability that the trial result is correct.

For planning at 100% of the observed effect, the illustration gives 111 participants per arm for 80% power and 148 participants per arm for 90% power. For planning at 75% of the observed effect, it gives 177 participants per arm for 80% power and 236 participants per arm for 90% power. For planning at 50% of the observed effect, it gives 352 participants per arm for 80% power and 471 participants per arm for 90% power. Smaller effects require more participants to detect under the stated assumptions.

These figures are not observed power. The original trial’s own sample-size justification and design assumptions are not reported in the registry record. The illustration should therefore be read as a planning aid based on the observed estimate, which itself is uncertain, rather than as a description of the trial’s intended enrollment target or as evidence about whether the completed study was adequately powered.

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 = 0.929; treatment proportion p₁ = 0.800; average p̄ = 0.864.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4843 = 0.9493.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4757 = 0.4004.
4. n = (0.9493 + 0.4004)² / (-0.1286)² = 110.2, rounded up to 111 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 <- 0.928571428571429                          # control proportion
p1 <- 0.8                          # 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(2214420)
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 = 111 (80% power), 148 (90% power)
 75% of observed effect: n per arm = 177 (80% power), 236 (90% power)
 50% of observed effect: n per arm = 352 (80% power), 471 (90% power)
power.prop.test: 110.2 
Simulated power at n = 111 per arm: 0.823 (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 one primary outcome measure, SVR12, and no secondary outcomes. It does not report a complete statistical analysis plan, a prespecified hierarchy of outcomes, or a multiplicity adjustment procedure. The comparison includes an unadjusted p-value of 0.348. Whether any other testing was planned or performed is not reported in the registry record, so the impact of multiple testing cannot be assessed from the posted information.

Missing-data handling is also not described. The reported outcome counts are 13 of 14 in SMV+SOF and 8 of 10 in SMV+SOF+RBV, but the registry does not explain whether the denominators reflect all randomized participants, participants with available follow-up, or another analysis population. It does not state how treatment discontinuations, missed assessments, or unavailable HCV RNA measurements were classified or handled.

The record identifies randomized allocation but does not specify whether the comparison used an intention-to-treat, modified intention-to-treat, per-protocol, or other analysis population. The randomization sequence method, allocation concealment, baseline-adjusted analyses, subgroup analyses, and interim analyses are not reported in the registry record. These omissions limit assessment of how closely the posted comparison followed a prespecified statistical plan.

In general, multiplicity is the increased chance of a false-positive finding when several hypotheses are tested. Missing outcomes can also affect interpretation if their occurrence or handling is related to treatment or outcome. Those are general methodological concerns; the registry does not provide enough detail to determine whether either issue materially changed this trial’s result.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events among 14 participants at risk in the SMV+SOF arm and zero among 10 participants at risk in the SMV+SOF+RBV arm. It lists no serious adverse event terms. The death counts are not reported in the registry record.

For other adverse events, the record reports 13 affected participants among 14 at risk in SMV+SOF and 9 affected participants among 10 at risk in SMV+SOF+RBV. These are counts of participants reported as affected, not a description of the number, type, duration, or severity of each event. The registry does not provide event terms for these other adverse events in the listed results.

In general, safety counts need context about how events were defined, collected, attributed, and followed. Such details, including the monitoring period and whether an event could be counted more than once, are not reported in the registry record. The figures describe the recorded participants and should not be interpreted as establishing that no serious events could occur or as a complete comparison of safety between arms.

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

The posted results show SVR12 in 13 of 14 participants assigned to SMV+SOF and 8 of 10 assigned to SMV+SOF+RBV. The registry’s estimated risk difference is -0.129 for the ribavirin arm relative to the arm without ribavirin, with a confidence interval from -0.411 to 0.154. The point estimate favors the arm without ribavirin on this endpoint, but the uncertainty interval includes zero and values in either direction. The unadjusted p-value is 0.348.

These data do not establish that adding ribavirin improves or worsens SVR12, and they do not establish that the regimens are equivalent. A failure to meet a conventional statistical significance threshold is not proof of no difference. Establishing equivalence or non-inferiority requires an appropriate prospective design and a defined margin; neither is reported in the registry record.

The findings apply directly to the trial participants and the recorded endpoint at the stated follow-up time. The record describes the population as interferon-intolerant or ineligible patients with chronic hepatitis C, but additional information about eligibility, genotype composition, baseline characteristics, adherence, and missing follow-up is not reported. Generalizing beyond the enrolled participants therefore requires caution.

The registry’s description says that SVR12 is generally indicative of hepatitis C infection being cured. The posted primary result, however, is specifically an RNA-based outcome at 12 weeks after treatment. It does not by itself report longer-term follow-up, other clinical outcomes, or individual treatment experience. These statistics describe the observed trial comparison; they are not medical advice and do not determine what treatment is suitable for a particular person.

16. Why This Trial Matters Statistically

This trial is statistically informative as a randomized comparison of two treatment regimens in an identified population, with a clearly defined binary endpoint and a specified follow-up time. It compares simeprevir plus sofosbuvir with the same regimen plus ribavirin, and it reports arm-level SVR12 counts as well as absolute and relative effect estimates.

The main statistical lesson is the distinction between an observed difference and a precise estimate of a difference. The risk-difference point estimate is -0.129, but its interval extends from -0.411 to 0.154. That range includes no difference and effects in either direction. The p-value of 0.348 does not settle whether a meaningful difference exists. Effect size, uncertainty, and study design all matter to interpretation.

The sample is small, with 14 participants in one arm and 10 in the other. This helps explain why the estimates are imprecise and why planning calculations based on the observed effect yield much larger illustrative group sizes. The planning illustrations are not evidence of the trial’s original design or of its observed power; the original sample-size justification is not reported in the registry record.

The record also illustrates why registry results need to be read with attention to reporting completeness. The outcome counts and comparison estimates are available, while analysis-population definitions, missing-data handling, and detailed statistical methods are not reported. Those details affect how confidently readers can assess the robustness and scope of the comparison. Reporting the estimate alongside its uncertainty, and distinguishing a nonsignificant result from evidence of equivalence, are central to sound statistical interpretation.

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.

The enrolled sample was 24 participants, divided between arms with 14 and 10 participants. Those counts limit the precision of the between-arm estimates. The confidence intervals are broad, and the trial result does not resolve the direction or size of the underlying difference in SVR12 with confidence.

The registry record does not report the randomization sequence method, allocation concealment, analysis population, or a full statistical analysis plan. It also does not report how missing endpoint measurements or treatment discontinuations were handled. Without those details, the potential effects of departures from assigned treatment or unavailable follow-up cannot be assessed.

The trial was unmasked. The primary endpoint is based on an HCV RNA result, but the registry does not describe the laboratory assessment process or whether outcome assessment was conducted without knowledge of treatment assignment. Other aspects of the trial context, including sites, baseline characteristics, adherence, and detailed eligibility criteria, are not reported in the registry record.

The outcome reporting is limited to one primary measure, with no secondary outcomes listed. The registry does not report longer-term outcomes, detailed adverse event terms beyond the serious-event listing, or death counts. Its original sample-size rationale, interim analyses, and any multiplicity plan are also not reported. These limitations constrain interpretation of precision, completeness, and generalizability; they do not change the reported counts, but they limit the conclusions that can be drawn from them.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: SMV + SOF With/Without RBV for IFN-II Patients With CHC — NCT02214420.
• Registry record last updated 2018-06-19; status last verified 2018-05.
• Results first posted 2018-05-17.
• 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

NCT02214420 is a completed Phase 4 randomized, unmasked, parallel-arm trial sponsored by SC Liver Research Consortium, LLC. It enrolled 24 participants with a record start of 2014-10 and primary completion of 2016-06. The comparison was 12 weeks of simeprevir plus sofosbuvir versus the same regimen with ribavirin in interferon-intolerant or ineligible patients with chronic hepatitis C.

The primary outcome was SVR12, defined as undetectable HCV RNA 12 weeks after treatment. The posted counts were 13 of 14 in SMV+SOF and 8 of 10 in SMV+SOF+RBV. The risk difference for the ribavirin arm relative to the other arm was -0.129, with a confidence interval from -0.411 to 0.154; the unadjusted p-value was 0.348. The comparison is imprecise, and the registry does not report the original sample-size justification, detailed analysis plan, or missing-data handling.