Efficacy and Safety of Alisporivir Alone or Combined With RBV or PEG in Chronic Hepatitis C Genotype 2 and 3 Treatment-naïve Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Alisporivir Alone or Combined With RBV or PEG in Chronic Hepatitis C Genotype 2 and 3 Treatment-naïve Participants (NCT01215643), a randomized phase 2 study. The primary outcome is Percentage of Participants With Rapid Viral Response (RVR) After 4 Weeks of Treatment < the Limit of Quantification (RVR4LOQ).

2. Clinical Question

The clinical question is framed around early viral response rather than a later outcome such as response after treatment completion. The trial compares several distinct regimens, so the results are relevant to each specified treatment contrast rather than to a single pooled comparison of all alisporivir regimens. The posted primary comparisons use ALV 1000 mg as their reference, while the study description identifies PEG+RBV as standard of care. Those are different reference points and should not be conflated.

The registry describes additional treatment for participants who did not achieve rapid viral response, but the posted primary endpoint remains the response measured after four weeks. The record does not report enough detail to determine how that later treatment pathway affected the primary comparison. The findings therefore address the recorded early virologic outcome and its uncertainty, not every aspect of the treatment strategy.

3. Trial Design

This was a randomized, open-label, parallel-group phase IIB study. The registry lists enrollment of 340 and status as completed. The study began in 2010-10, with primary completion in 2012-05. Participants were treatment-naïve and had hepatitis C genotype 2 or 3. The record lists Hepatitis C and Chronic Pain among the conditions.

Five treatment groups are described. ALV 1000 mg consisted of alisporivir 600 mg twice daily for one week, followed by 1000 mg once daily during Weeks 2 to 24. In the ALV 600 mg+RBV and ALV 800 mg+RBV groups, alisporivir 600 mg twice daily with ribavirin was used for one week, followed by the named alisporivir dose once daily with ribavirin during Weeks 2 to 24. The ALV 600 mg+PEG group used alisporivir 600 mg twice daily with peginterferon alfa-2a for one week, followed by alisporivir 600 mg once daily with peginterferon alfa-2a once weekly during Weeks 2 to 24. PEG+RBV consisted of peginterferon alfa-2a and ribavirin during Weeks 1 to 24.

Randomization supports comparisons between assigned groups, while the open-label design means masking was not used. The registry record does not report allocation concealment, the randomization procedure, stratification factors, or a detailed schedule of visits and assessments. The study description says triple therapy with alisporivir plus standard of care would be applied to participants not achieving rapid viral response in the different arms. Further details of that treatment rule and its implementation are not reported in the registry record.

The primary endpoint population is described as the Full Analysis Set, defined as participants to whom study treatment was correctly assigned. This definition should be kept in mind when interpreting denominators: the registry reports outcome-specific group sizes, and those are not always identical to the safety-group denominators. The original sample-size justification and the trial's own design assumptions are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS), defined as all participants to whom study treatment was correctly assigned.

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: All randomized participants

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Rapid Viral Response (RVR) After 4 Weeks of Treatment < the Limit of Quantification (RVR4LOQ), measured over after 4 weeks of treatment.

The primary endpoint is the percentage of participants with rapid viral response after four weeks of treatment, defined as serum HCV RNA below the limit of quantification. The registry specifies the limit as < 25 IU/mL. A lower laboratory measurement than that threshold is treated as meeting the endpoint definition; the measure is a binary outcome for each participant and is summarized as a percentage within each group.

Rapid viral response is used as an early marker of virologic response during treatment. It captures whether the assay result has crossed a prespecified threshold at an early treatment time, rather than measuring the magnitude of each participant's viral-load change. This makes the result straightforward to express as the fraction meeting the response definition, but it also means the outcome does not describe how far below the threshold a measurement lies.

The endpoint is time-specific and definition-specific. A result below the limit of quantification is not interchangeable with a result below the limit of detection, which is a separate secondary outcome in the registry. Nor does this primary measure by itself establish a later response after treatment or provide information about longer-term clinical outcomes. Interpretation should therefore remain tied to the four-week assessment, the stated threshold, and the Full Analysis Set definition. The registry record does not report additional assay-performance details or how measurements at the threshold were handled beyond the stated definition.

7. Results Posted in the Registry

• ALV 600 mg+RBV: 36.9% (31/84) versus 28.4% (23/81) on control; risk difference 8.5 percentage points (95% CI -5.7 to 22.8), risk ratio 1.30 (0.83–2.03); unadjusted two-proportion z-test p = 0.244.
• ALV 800 mg+RBV: 41.9% (39/93) versus 28.4% (23/81) on control; risk difference 13.5 percentage points (95% CI -0.5 to 27.6), risk ratio 1.48 (0.97–2.25); unadjusted two-proportion z-test p = 0.063.
• ALV 600 mg+PEG: 84.6% (33/39) versus 28.4% (23/81) on control; risk difference 56.2 percentage points (95% CI 41.2 to 71.2), risk ratio 2.98 (2.06–4.32); unadjusted two-proportion z-test p = <0.001.
• PEG+RBV: 72.5% (29/40) versus 28.4% (23/81) on control; risk difference 44.1 percentage points (95% CI 27.1 to 61.1), risk ratio 2.55 (1.72–3.79); unadjusted two-proportion z-test p = <0.001.

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 RVR After 4 Weeks of Treatment < the Limit of Detection (RVR4LOD)

• 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:
  • ALV 600 mg+RBV: 14.3% (12/84) versus 18.5% (15/81) on control; risk difference -4.2 percentage points (95% CI -15.5 to 7.1), risk ratio 0.77 (0.38–1.55); unadjusted two-proportion z-test p = 0.463.
  • ALV 800 mg+RBV: 23.7% (22/93) versus 18.5% (15/81) on control; risk difference 5.1 percentage points (95% CI -7.0 to 17.2), risk ratio 1.28 (0.71–2.29); unadjusted two-proportion z-test p = 0.409.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between ALV 600 mg+RBV 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 ALV 800 mg+RBV and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With On-treatment Viral Breakthrough

• 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:
  • ALV 600 mg+RBV: 3.6% (3/84) versus 2.5% (2/81) on control; risk difference 1.1 percentage points (95% CI -4.1 to 6.3), risk ratio 1.45 (0.25–8.43); unadjusted two-proportion z-test p = 0.680.
  • ALV 800 mg+RBV: 2.2% (2/93) versus 2.5% (2/81) on control; risk difference -0.3 percentage points (95% CI -4.8 to 4.2), risk ratio 0.87 (0.13–6.04); unadjusted two-proportion z-test p = 0.889.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between ALV 600 mg+RBV 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 ALV 800 mg+RBV and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the four-week primary response question to other virologic definitions and time points, and include on-treatment viral breakthrough. The registry lists outcomes based on response below the limit of detection, response by genotype, complete early viral response after twelve weeks, and end-of-treatment response within twenty-four weeks. These measures are related to the primary endpoint because they track virologic status during treatment, but they use different thresholds, timing, or subgroup definitions. They should not be treated as interchangeable replications of the primary outcome.

The posted secondary values show variation across treatment groups and outcomes. In broad terms, the groups containing peginterferon alfa-2a have higher posted percentages for the early response outcomes than the alisporivir-alone and alisporivir-plus-ribavirin groups, while the breakthrough outcome is uncommon across groups. That overall pattern is context for the primary result, not an independent confirmation of every primary contrast. The registry record does not provide a complete set of comparison analyses for all listed secondary outcomes.

Secondary outcomes are often useful for describing response patterns, checking whether effects persist across related definitions, and identifying questions for further study. Their evidential weight is limited when many outcomes and treatment contrasts are examined without a reported multiplicity strategy. Even if an individual unadjusted comparison appears notable, the chance of at least one apparently unusual result rises as more comparisons are considered. The statistical analysis plan, hierarchy of outcomes, and any adjustment for multiplicity are not reported in the registry record.

Genotype-specific outcomes may also involve smaller subsets than the overall endpoint, which can reduce precision. The registry lists genotype-specific secondary outcomes but does not provide all corresponding results in the record summarized for this analysis. The secondary evidence should therefore be read as supportive descriptive context, with the primary endpoint remaining the principal focus and with due caution about endpoint definitions, subgroup sizes, and unadjusted testing.

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

• Percentage of Participants With RVR After 4 Weeks of Treatment < the Limit of Detection (RVR4LOD)
• Percentage of Participants With RVR4LOQ and RVR4LOD (Genotype 2)
• Percentage of Participants With RVR4LOQ and RVR4LOD (Genotype 3)
• Percentage of Participants With Complete Early Viral Response (cEVR) After 12 Weeks of Treatment (cEVR12LOQ and cEVR12LOD)
• Percentage of Participants With cEVR12LOQ and cEVR12LOD (Genotype 2)
• Percentage of Participants With cEVR12LOQ and cEVR12LOD (Genotype 3)
• Percentage of Participants With End of Treatment Response (ETR) Within 24 Weeks (ETR24LOQ and ETR24LOD)
• Percentage of Participants With ETR24LOQ and ETR24LOD (Genotype 2)

9. Statistical Interpretation

10. Statistical Methods Explained

For a binary endpoint, each participant either meets the response definition or does not. The group percentage is the proportion meeting that definition, expressed as a percentage. The primary endpoint used the threshold of HCV RNA below the limit of quantification after four weeks. This summary is useful because it preserves the clinical threshold in the outcome definition, but it compresses each participant's laboratory measurement into a yes-or-no classification.

What does a risk difference describe?

A risk difference compares the event proportions in two groups by subtracting one group proportion from the other. It is expressed on the absolute probability scale. A value above zero in these posted contrasts means the response proportion was higher in the named group than in ALV 1000 mg; a value below zero means it was lower. The reported estimates are simple unadjusted recalculations from posted summary statistics, not adjusted estimates from a model reported by the registry. The confidence interval describes uncertainty in that contrast.

Other effect measures can express the same comparison in relative terms, such as a risk ratio or odds ratio. Relative measures answer a different question from an absolute difference and can appear more pronounced when the baseline probability is low. No single measure replaces the need to examine the group percentages, absolute contrast, and uncertainty together. The posted result includes other measures, but the primary interpretation is based on the risk difference and its confidence interval.

How should p-values be read?

A p-value describes how unusual data at least as incompatible with a specified null hypothesis would be under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The displayed p-values are unadjusted. They do not account for considering several treatment contrasts or multiple outcomes, and the registry record does not report an adjustment procedure. The p-value should therefore be considered alongside the estimate and interval, not as a stand-alone decision rule.

A confidence interval is an interval estimate formed using a statistical procedure with stated assumptions. Its width reflects precision: narrower intervals indicate less statistical uncertainty than wider intervals, all else equal. If an interval for a risk difference includes zero, the data are compatible with no difference under the corresponding interval procedure. That does not prove equivalence. Conversely, an interval that excludes zero does not establish that a difference is clinically important, unbiased, or replicated.

What do the posted calculations represent?

The registry lists group response percentages and group sizes, and the comparisons are recalculated from those posted summaries without covariate adjustment. They are not identified as the sponsor's adjusted analysis. The registry record lists no reported analyses for the secondary outcomes and does not report a detailed primary statistical model. It also does not report whether the primary analysis used a prespecified test, how missing endpoint measurements were handled, or whether any sensitivity analyses were performed.

Randomization is intended to make treatment groups comparable on average, including with respect to measured and unmeasured baseline characteristics. It does not ensure that every group is balanced in a particular realized sample, especially when groups are modest in size. An unadjusted comparison is therefore interpretable as a direct comparison of observed group proportions, while any claim about adjusted treatment effects would require an analysis not reported in the registry record.

Why can sparse outcomes be difficult to interpret?

When an outcome occurs rarely, a small change in the number of observed events can substantially affect a percentage or relative measure. Estimates can consequently be unstable, and confidence intervals may be wide. This is especially relevant to rare events such as viral breakthrough in the posted secondary outcomes. A zero observed event proportion in a group does not establish that the underlying event probability is zero. The registry record does not provide a detailed model for those rare-event comparisons.

The trial's open-label design is also relevant. Laboratory-defined virologic outcomes are more objective than outcomes requiring subjective judgment, but open-label conduct can still affect adherence, co-interventions, follow-up, or decisions about additional treatment. The record does not report enough operational detail to assess those pathways. Statistical interpretation should distinguish what the observed outcome and unadjusted comparison say from questions about implementation, missing data, and broader clinical meaning that require further information.

11. Confidence Intervals and Precision

The primary group percentages are point estimates, and their precision depends partly on the number of participants contributing to each result and on the observed response frequency. The registry gives outcome group sizes of 81.0 for ALV 1000 mg, 84.0 for ALV 600 mg+RBV, 93.0 for ALV 800 mg+RBV, 39.0 for ALV 600 mg+PEG, and 40.0 for PEG+RBV. The comparison intervals reflect uncertainty in the contrasts, not uncertainty in a clinical decision.

For the two ribavirin combinations compared with ALV 1000 mg, the risk-difference intervals extend across zero: -0.057 to 0.228 for ALV 600 mg+RBV, and -0.005 to 0.276 for ALV 800 mg+RBV. This means the recalculated contrasts do not precisely distinguish a positive difference from no difference at the interval's stated confidence level. The interval for ALV 800 mg+RBV comes close to zero, but closeness is not a substitute for the full interval or a prespecified decision rule.

The intervals for the PEG-containing groups exclude zero: 0.412 to 0.712 for ALV 600 mg+PEG, and 0.271 to 0.611 for PEG+RBV. They still cover a range of possible differences, so the point estimates should not be treated as exact effect sizes. The smaller group sizes in these contrasts contribute to uncertainty even where the observed differences are large.

In general, a confidence interval communicates both direction and precision. It does not account automatically for all sources of uncertainty, including missing outcomes, analysis choices, or multiplicity. The registry record does not report adjusted confidence intervals or the method used for the original sponsor analysis. These recalculated intervals should be interpreted as unadjusted summaries of the posted data.

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 figures are planning illustrations based on the observed effect, not a record of the trial's original design calculations. For these binary outcomes, the listed figures are participants per arm, not total participants across a trial. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers an effect to detect equal to the stated fraction of the observed effect. The trial's own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm under those assumptions for a design with an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column gives the corresponding planning estimate for a design with a 90% chance. These are design calculations, not guarantees about a future study, and they do not account for every practical or analytic feature that could affect results. They are not observed power.

Smaller target effects require more participants because subtle differences are harder to distinguish from random variation. Thus the rows that plan for 75% or 50% of the observed effect generally require more participants per arm than the row that plans for 100% of that effect. The numbers can change substantially with the assumed effect size, especially when the observed contrast is small. Since the estimates use observed effects, they should not be taken as reliable proof that the same effect will recur in another study. They are best read as illustrations of how planning requirements depend on the effect selected and the desired power.

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 = 0.284; treatment proportion p₁ = 0.369; average p̄ = 0.326.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6632 = 1.2998.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6604 = 0.5558.
4. n = (1.2998 + 0.5558)² / (0.0851)² = 475.5, rounded up to 476 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 <- 0.283950617283951                          # control proportion
p1 <- 0.369047619047619                          # 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(1215643)
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 = 476 (80% power), 637 (90% power)
 75% of observed effect: n per arm = 832 (80% power), 1,113 (90% power)
 50% of observed effect: n per arm = 1,838 (80% power), 2,460 (90% power)
power.prop.test: 475.5 
Simulated power at n = 476 per arm: 0.801 (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. Multiplicity, Missing Data and Analysis Populations

The study includes multiple treatment groups, multiple pairwise contrasts, and numerous outcome measures. Each additional comparison creates another opportunity to observe an apparently unusual result by chance. The primary comparisons presented are unadjusted, and the registry record does not report a multiplicity adjustment, a prespecified testing hierarchy, or which comparisons were intended to be confirmatory. The p-values therefore describe individual unadjusted comparisons and should not be interpreted as controlling the overall false-positive risk across the full set of outcomes and contrasts.

The record lists an endpoint population definition for the primary outcome: the Full Analysis Set consists of participants to whom study treatment was correctly assigned. It does not report the full analysis populations used for every secondary outcome, or whether all randomized participants were included in each analysis. The primary outcome group sizes are not identical to the safety-group denominators. Reasons for those differences, including exclusions or missing measurements, are not reported in the registry record.

Missing data can affect binary outcomes if the probability of having an observed measurement differs between groups or depends on response status. The registry record does not report the amount or pattern of missing primary endpoint data, the handling of missing values, or sensitivity analyses assessing alternative assumptions. It also does not report whether participants with treatment discontinuation or protocol deviations were included in each analysis. Without that information, it is not possible to assess how strongly missingness or analysis-population choices might affect the estimates.

The record does not report a detailed statistical analysis plan, the primary hypothesis-testing procedure, covariate adjustment, interim analyses, or stopping rules. These omissions do not change the reported percentages, but they limit the ability to determine whether each analytic choice was prespecified. Interpretations should accordingly focus on the posted group summaries and their unadjusted uncertainty, rather than assuming unreported protections against multiplicity, missing data, or selective analysis.

15. 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: pyelonephritis (2.7%), toxicity to various agents (2.7%), retinopathy (2.6%), pneumonia (2.6%), alcohol poisoning (2.6%).

The registry reports on-treatment and post-treatment adverse-event groups separately. For each group, it lists the number at risk and the number affected by serious adverse events and by other adverse events. For example, on treatment, the serious-event counts range from 1 in ALV 600 mg+RBV to 9 in ALV 800 mg+RBV; the corresponding at-risk counts are 84 and 94. The other-event counts are reported separately and should not be confused with serious events. These are counts, not comparative risk estimates.

Post-treatment serious adverse-event counts are also reported, including 0 for ALV 600 mg+PEG and 0 for PEG+RBV. A zero recorded count does not establish that risk is absent. The registry record does not report deaths for these groups. The listed serious adverse-event terms include Pyelonephritis and Toxicity to various agents at 2.7%, and Retinopathy, Pneumonia, Alcohol poisoning, and Head injury at 2.6% each.

These safety summaries do not establish that one regimen is safer than another. The record does not provide adjusted comparisons, event timing detail, or a fuller account of severity and relatedness for the listed terms. Different group sizes and the distinction between on-treatment and post-treatment follow-up matter when reading the counts.

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

The posted results describe the percentage of participants meeting an early virologic threshold after four weeks in each assigned treatment group. They show that the observed response percentages differed across the regimens, and that the unadjusted contrasts against ALV 1000 mg were not equally precise. The comparisons involving ALV 600 mg+RBV and ALV 800 mg+RBV have confidence intervals that include zero; those involving ALV 600 mg+PEG and PEG+RBV have intervals that exclude zero. These are statements about the posted data and their statistical uncertainty, not medical advice.

The results do not establish that a regimen produces a particular long-term outcome. RVR4LOQ is an early, threshold-based laboratory measure. It does not by itself describe end-of-treatment response, sustained response, symptoms, complications, or quality of life. The registry lists other virologic outcomes, but they do not replace evidence about outcomes that are not reported in the record. Nor does an observed early difference demonstrate why the groups differed.

The results also do not establish equivalence where an interval includes zero. An imprecise estimate can be compatible with both no difference and effects in either direction over the range covered by its interval. Similarly, a statistically notable unadjusted contrast does not guarantee a clinically important effect or eliminate the possibility of bias, chance, or differences in implementation. The trial is randomized, but open-label conduct and limited reporting about analysis and missing outcomes constrain what can be concluded.

Finally, the estimates apply to the study population and treatment regimens described in the registry. They should not be generalized automatically to people with other hepatitis C genotypes, prior treatment, or different regimens. The record does not report the details needed to evaluate every eligibility restriction or subgroup. The defensible interpretation is therefore limited to the recorded early virologic outcome, the specified groups, and the uncertainty shown by the posted comparisons.

17. Why This Trial Matters Statistically

This study is statistically informative because it compares several active regimens rather than presenting a single treatment contrast. That structure makes the reference group important: the posted primary comparisons are against ALV 1000 mg, while PEG+RBV is described as standard of care. A reader asking whether a regimen differs from standard of care should not mistake the reported ALV 1000 mg contrasts for that comparison. The choice of comparator changes the question being answered.

The endpoint also illustrates why outcome definitions matter. RVR4LOQ uses a particular laboratory threshold at a particular treatment time. The registry separately lists a response below the limit of detection, and later response measures. A statistical contrast is meaningful only in relation to the precise definition and time point being compared; one threshold cannot be substituted for another without changing the clinical question.

There is also a useful distinction between the size of a point estimate and its precision. Some observed risk differences are large and their intervals exclude zero, while other contrasts have intervals spanning zero. The interval is essential context, particularly when group sizes differ. The study therefore illustrates how a result can vary across treatment regimens and how conclusions depend on both the estimated effect and uncertainty, rather than on a p-value alone.

Finally, the record's limited reporting of multiplicity, missing data, and the original analysis plan demonstrates why registry results need to be interpreted with attention to what is and is not documented. The posted data support descriptive comparisons of early response and safety counts. They do not answer every question about longer-term benefit, comparative safety, or generalizability.

18. 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 primary outcome is an early laboratory endpoint, so it cannot by itself establish later virologic response or broader clinical outcomes. The registry record lists additional virologic outcomes, but the available record does not provide a complete set of corresponding results and analyses. The clinical meaning of a four-week response therefore remains bounded by its stated definition and timing.

Five groups create several possible contrasts, and the registry record does not report a multiplicity adjustment or testing hierarchy. The primary comparison set and confirmatory status of each contrast are not reported. Secondary findings also involve multiple definitions and time points, which makes isolated unadjusted results less persuasive.

The study was open-label, and the registry does not report details of allocation concealment, adherence, treatment discontinuation, or co-interventions. The record describes additional triple therapy for participants who did not achieve rapid viral response but does not provide enough detail to assess its implementation or influence on later outcomes. The handling and extent of missing endpoint measurements are also not reported.

Outcome and safety denominators differ across reported groups. The registry does not explain those differences or provide enough detail to assess exclusions and analysis-population choices beyond the stated Full Analysis Set definition. The original sample-size rationale and the trial's own statistical plan are not reported. These limitations make the recalculated comparisons useful descriptive summaries, but they do not substitute for a complete trial analysis report.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of Alisporivir Alone or Combined With RBV or PEG in Chronic Hepatitis C Genotype 2 and 3 Treatment-naïve Participants — NCT01215643.
• Registry record last updated 2016-08-30; status last verified 2016-07.
• Results first posted 2016-08-30.
• 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.

22. Record Summary

NCT01215643 is a completed randomized, open-label, parallel-group phase IIB study of alisporivir alone or with ribavirin or peginterferon alfa-2a, compared with peginterferon alfa-2a plus ribavirin. The registry reports enrollment of 340 and a primary endpoint of rapid viral response after four weeks, defined as HCV RNA below the limit of quantification in the Full Analysis Set.

The posted response percentages vary across the five treatment groups. Unadjusted recalculated comparisons against ALV 1000 mg have confidence intervals that include zero for the ribavirin combinations and exclude zero for the PEG-containing groups. The registry also reports secondary virologic outcomes and on-treatment and post-treatment adverse-event counts. Multiplicity procedures, missing-data handling, the detailed analysis plan, and the original sample-size justification are not reported in the registry record.