A Study of Debio 025 in Combination With PegIFN Alpha-2a and Ribavirin in Chronic HCV Patients Non-responders to Standard Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Debio 025 in Combination With PegIFN Alpha-2a and Ribavirin in Chronic HCV Patients Non-responders to Standard Treatment (NCT00537407), a randomized phase 2 study. The primary outcome is Change From Baseline in log10 Hepatitis C Virus RNA at Day 29 in the Debio 025 Triple Therapy Treatment Arms (A, D, and E).

2. Clinical Question

The study was intended to assess viral kinetics, safety, and pharmacokinetics for different Debio 025 dosing regimens alongside peginterferon alpha-2a and ribavirin. The registry record describes the population as patients with chronic HCV genotype 1 who had not responded to standard peginterferon alpha and ribavirin treatment. Its question is therefore focused on treatment response in this particular group, rather than on people with other HCV genotypes or patients without the stated treatment history.

The primary result concerns the mean change in HCV RNA in the first 29 days. Secondary outcomes include RNA at Day 29 and response measures at later time points. Those measures address different aspects and durations of response, so the short-term primary endpoint should not be treated as a substitute for sustained viral response.

3. Trial Design

The registry record describes a randomized, open-label, 5-arm, parallel-group phase 2 study. It lists enrollment of 50 and a completed status. The study start is recorded as 2007-09, and primary completion as 2010-04. Masking is listed as none. The sponsor is Debiopharm International SA.

All five arms used Debio 025 at some point, but the regimens were not identical. Treatment Arms A, D, and E combined Debio 025 with peginterferon alpha-2a and ribavirin during the initial 29 days. Arm A used Debio 025 400 mg once daily, while Arm D used 800 mg once daily. Arm E began with a loading dose of 400 mg twice daily for 7 days and then used 400 mg/day for 22 days. The primary endpoint compares the triple-therapy arms A, D, and E.

Arms B and C varied the medicines combined with Debio 025 during the first 29 days. Arm B used Debio 025 alone during that period, and Arm C combined Debio 025 with peginterferon alpha-2a but not ribavirin. Their descriptions then specify peginterferon alpha-2a and ribavirin after the initial period. The described later treatment for Arms A through D continued peginterferon alpha-2a and ribavirin for 44 or 68 weeks depending on response. Arm E’s description does not include the same later-treatment duration detail, which is not reported in the registry record.

Random allocation supports comparison among assigned regimens, but the open-label design means treatment assignment was not masked. The registry record does not report the allocation procedure, the original sample-size justification, or a detailed statistical analysis plan. It also does not report an untreated or placebo group for the primary endpoint. The displayed comparisons should therefore be understood as comparisons between the listed active regimens, not as estimates against no treatment.

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.

Part 1 Weeks 1-4

Part 2 Weeks 5-48 or 72

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat population: All randomized participants with at least a Baseline and 1 on- or post-treatment hepatitis C virus RNA assessment.

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: Intent-to-treat population: All randomized participants with at least a Baseline and 1 on- or post-treatment hepatitis C virus RNA assessment.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in log10 Hepatitis C Virus RNA at Day 29 in the Debio 025 Triple Therapy Treatment Arms (A, D, and E), measured over Baseline to Day 29.

The primary endpoint is change from baseline to Day 29 in plasma HCV RNA, expressed in log10(IU/mL), for the Debio 025 triple-therapy arms A, D, and E. The registry record says HCV RNA was quantified in plasma samples using real time polymerase chain reaction. The reported outcome is a mean, with standard deviation as the measure of dispersion.

A change score describes how the measured RNA level shifted from a participant’s baseline over the specified period. Because the endpoint uses a logarithmic scale, differences in the reported means are differences on that scale; they should not be read as direct differences in raw IU/mL. Negative mean changes indicate that measured RNA was lower at follow-up than at baseline on average. The registry record does not give individual participant measurements or the distribution of changes.

General statistical context: an early change in a biological measurement can be useful for describing short-term response and comparing treatment regimens. It does not, by itself, establish that a response will persist after treatment ends. The registry record lists separate later response outcomes, including sustained viral response 24 weeks after treatment, but those outcomes are distinct from the Day 29 primary endpoint.

The stated primary analysis population includes randomized participants with a baseline and at least one on- or post-treatment HCV RNA assessment. This definition makes the availability of RNA measurements relevant to inclusion in the primary analysis. Details of how missing measurements were handled are not reported in the registry record.

7. Results Posted in the Registry

• Treatment Arm D: mean -2.32 versus -0.88 on control; difference -1.44 (95% CI -2.54 to -0.34), standardized effect d = -1.14; z-test p = 0.010.
• Treatment Arm E: mean -2.02 versus -0.88 on control; difference -1.14 (95% CI -2.21 to -0.07), standardized effect d = -0.93; z-test p = 0.037.

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.

log10 Hepatitis C Virus RNA at Day 29

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Treatment Arm C: mean 5.83 versus 5.57 on control; difference 0.26 (95% CI -0.50 to 1.02), standardized effect d = 0.30; z-test p = 0.504.
  • Treatment Arm D: mean 4.00 versus 5.57 on control; difference -1.57 (95% CI -2.66 to -0.48), standardized effect d = -1.26; z-test p = 0.005.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment Arm C and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Treatment Arm D than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Participants With an Early Viral Response at Week 12

• 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:
  • Treatment Arm C: 27.3% (3/11) versus 30.0% (3/10) on control; risk difference -2.7 percentage points (95% CI -41.4 to 36.0), risk ratio 0.91 (0.24–3.51); unadjusted two-proportion z-test p = 0.890.
  • Treatment Arm D: 70.0% (7/10) versus 30.0% (3/10) on control; risk difference 40.0 percentage points (95% CI -0.2 to 80.2), risk ratio 2.33 (0.83–6.54); unadjusted two-proportion z-test p = 0.074.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment Arm C 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 Treatment Arm D and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With an End-of-treatment Response at the End of Treatment (Week 48 or 72)

• 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:
  • Treatment Arm C: 18.2% (2/11) versus 20.0% (2/10) on control; risk difference -1.8 percentage points (95% CI -35.5 to 31.9), risk ratio 0.91 (0.16–5.30); unadjusted two-proportion z-test p = 0.916.
  • Treatment Arm D: 10.0% (1/10) versus 20.0% (2/10) on control; risk difference -10.0 percentage points (95% CI -41.0 to 21.0), risk ratio 0.50 (0.05–4.67); unadjusted two-proportion z-test p = 0.531.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Treatment Arm C 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 Treatment Arm D and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary results cover Day 29 RNA, early viral response at Week 12, and end-of-treatment response at Week 48 or 72. Across these measures, estimates vary among the five arms rather than forming one uniformly ordered pattern. Some comparisons show arm-level values in the direction of greater short-term response, while later response percentages do not consistently mirror that pattern. The outcome summaries also include secondary endpoint titles for rapid viral response and sustained viral response 24 weeks after treatment, but their numerical results are not reported in the registry record.

This broad pattern is relevant to the primary result because it cautions against treating a more negative short-term mean RNA change as proof of a better outcome at later follow-up. The endpoints differ in what they measure, when they are assessed, and whether they are continuous or percentage outcomes. A short-term viral-kinetics difference and a later response proportion are related questions, but neither can replace the other.

The record lists comparisons for selected secondary outcomes, but no sponsor-reported analyses are available in the registry record. The secondary comparison p-values are unadjusted, and the registry record does not report a multiplicity plan. General statistical context: when several outcomes or group comparisons are examined, the chance of seeing an apparently unusual result by chance can increase. Without a reported adjustment or prespecified hierarchy, secondary p-values are best regarded as exploratory signals rather than standalone confirmation.

Small group sizes further limit the stability of percentages and comparisons. A percentage can move substantially when a small number of outcome classifications change, and its uncertainty may be wide even if a point estimate appears notable. The registry record does not report confidence intervals for the posted secondary percentages as registry analyses. The observed secondary pattern is therefore descriptive and should be read alongside the primary endpoint without elevating isolated comparisons above the overall evidence.

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

• Change From Baseline in log10 Hepatitis C Virus RNA at Day 29 in the Debio 025 Monotherapy and Dual Therapy Treatment Arms (B and C)
• log10 Hepatitis C Virus RNA at Day 29
• Percentage of Participants With a Rapid Viral Response at Day 29
• Percentage of Participants With an Early Viral Response at Week 12
• Percentage of Participants With an End-of-treatment Response at the End of Treatment (Week 48 or 72)
• Percentage of Participants With a Sustained Viral Response 24 Weeks After the End of Treatment (Week 72 or 96)

9. Statistical Interpretation

10. Statistical Methods Explained

General statistical context: a continuous outcome such as change in log10 HCV RNA is commonly summarized by a mean and a measure of spread. The mean describes the average observed change in an arm. The standard deviation describes how dispersed individual values are around that arm’s mean. A standard deviation is not the uncertainty in the mean itself; uncertainty in a comparison also depends on the amount of information in each arm.

The primary endpoint is reported as a mean change, and the posted pairwise comparisons are mean differences against Treatment Arm A. A mean difference is formed by contrasting the two arm means on the endpoint scale. A negative difference in this case corresponds to a more negative mean change in the comparison arm than in Arm A. The difference remains on the log10(IU/mL) scale and is not a raw-scale RNA difference.

The comparison summaries include confidence intervals. General statistical context: a confidence interval gives a range of values compatible with the data and the assumptions of the interval procedure. It conveys uncertainty about the estimated contrast, rather than the range of individual participant outcomes. A narrower interval indicates greater precision for that contrast; a wider interval indicates less precision. An interval that includes zero does not rule out a difference in either direction, while an interval excluding zero indicates that zero is not among the values covered by that interval procedure. Interpretation still depends on the design, analysis choices, and the number of comparisons being considered.

The posted p-values for the primary comparisons are unadjusted. General statistical context: a p-value describes how surprising data at least as incompatible with a specified null model would be if that model and the test assumptions were correct. It is not the probability that the null hypothesis is true, nor does it state the probability that a result will replicate. A p-value also does not communicate the size of the estimated effect; that is better conveyed by the estimate and its interval.

For these posted primary results, the comparisons are simple, unadjusted recalculations from summary statistics. They should not be confused with an undocumented sponsor model. The registry record does not report the sponsor’s detailed statistical methods, any covariate-adjusted model, or a prespecified multiplicity procedure. Because those choices can affect estimates and uncertainty, the recalculated results are a limited statistical reading of the posted arm summaries.

General statistical context: randomization is intended to make assigned groups comparable on average, but small groups can still differ by chance in baseline characteristics or other prognostic features. An open-label study also means that participants and study personnel knew assignment, as masking is listed as none. That fact does not alter the arithmetic of the mean difference, but it is part of the design context when interpreting outcomes and conduct. The registry record does not report details of allocation concealment, adherence, or how treatment changes were incorporated in the analysis.

The primary population is described as the intent-to-treat population comprising randomized participants with a baseline and at least one on- or post-treatment RNA assessment. This is the record’s stated definition, rather than a complete account of missing-data handling. General statistical context: excluding participants without qualifying measurements can affect what population a result represents, especially if measurement availability is related to response or tolerability. The registry record does not report imputation, sensitivity analyses, or the handling of participants who lacked the required RNA assessments.

The endpoint’s logarithmic scale matters. A mean difference on a log scale summarizes differences in logged measurements; it is not a percentage change or a raw-unit change unless an explicit transformation and interpretation are posted. No such additional transformation is reported in the registry record. The measure also captures change over the stated baseline-to-Day 29 timeframe, not the full course of treatment.

The secondary outcomes include continuous RNA summaries and percentages with response at later time points. General statistical context: continuous and binary outcomes use different estimands and uncertainty calculations. A percentage is an observed proportion among the analyzed participants for that outcome; its precision depends on the number of observations and the number meeting the response definition. With small groups and sparse response counts, percentage estimates can be unstable. No alternative modeling details for the secondary endpoints are reported in the registry record.

Sample-size illustrations use a separate, stated planning approach based on the observed effect, two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. They are hypothetical planning illustrations rather than an account of the original design. The original design assumptions are not reported in the registry record. General statistical context: planning estimates are sensitive to the assumed effect and variability, and using an observed effect from a small study can produce an uncertain planning target.

Finally, statistical significance and clinical importance are different questions. The primary comparison estimates and intervals characterize the observed Day 29 differences on the specified scale. They do not establish a benefit-risk judgment or a lasting outcome. The registry record contains no basis for extending the results beyond the stated population, regimens, endpoint, and reported follow-up.

11. Confidence Intervals and Precision

The primary mean difference for Treatment Arm D versus Treatment Arm A is -1.44 log10(IU/mL), with a 95% confidence interval from -2.543 to -0.338. The interval lies below zero, while still covering a range of possible mean differences. For Treatment Arm E versus Treatment Arm A, the estimate is -1.139, with a 95% confidence interval from -2.21 to -0.068. That interval also lies below zero, but likewise spans values with materially different magnitudes.

General statistical context: confidence intervals express uncertainty in an estimated contrast under the method’s assumptions. They are not guarantees that the true value falls within the particular observed interval, and they are not ranges containing a stated proportion of individual outcomes. Here, the arm-level standard deviations indicate substantial spread in individual changes relative to the precision available from the small groups. The registry record reports 10.0 participants in each primary arm.

The estimates therefore carry uncertainty about the size of the differences, even though both intervals exclude zero. The p-values and intervals address related questions but provide different information: the p-value is a test summary, while the interval makes a range of compatible effect sizes visible. Neither resolves uncertainties about multiplicity, unreported analysis choices, or whether the Day 29 measure predicts later response.

Precision is endpoint-specific. The primary interval concerns the mean change in log10 HCV RNA from baseline to Day 29, not later response percentages, safety outcomes, or sustained response. The registry record does not report confidence intervals for the posted arm-level means or for the secondary response percentages in the posted outcome summaries. Accordingly, precision for those outcomes cannot be inferred from the primary intervals.

12. Planning a Similar Trial: Sample Size

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

The sample-size illustrations are per arm for these two-arm comparisons. The record’s planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect equal to the stated fraction of the observed effect. The original trial design assumptions and sample-size justification are not reported in the registry record. These figures are planning illustrations, not observed power.

The 80% power column gives the estimated participants per arm for a hypothetical study planned to have an 80% chance of detecting the specified effect under those assumptions, if the assumed effect and model are appropriate. The 90% power column gives the corresponding planning estimate for a 90% chance. These are design targets, not guarantees that a future study will detect an effect and not estimates of the probability that the posted result is true.

Rows that plan for 100% of the observed effect use the full observed comparison as the assumed target; rows for 75% or 50% use smaller assumed effects. Smaller effects require more participants per arm to achieve the same planned power under the stated approach. This relationship is especially important when the observed effect may be unstable, as can happen with small groups. The calculations are based on the observed comparison and should not be mistaken for the study’s original recruitment target or a retrospective measure of its power.

The sample-size curve should be read as a visual representation of the same planning relationship between the assumed effect and required participants per arm. It does not add new evidence about efficacy. Planning estimates depend on assumptions about the effect, variability, allocation, significance level, and approximation method; the registry record does not report whether its original design used these same assumptions.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -1.440; pooled standard deviation σ = 1.258.
2. n = 2 × (1.96 + 0.842)² × 1.258² / -1.440² = 12.0, rounded up to 12 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
delta <- -1.44                      # observed difference in means
sigma <- 1.2578484348283                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(537407)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 12 (80% power), 17 (90% power)
 75% of observed effect: n per arm = 22 (80% power), 29 (90% power)
 50% of observed effect: n per arm = 48 (80% power), 65 (90% power)
power.t.test: 13 
Simulated power at n = 12 per arm: 0.769 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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 registry record includes a primary endpoint comparing three triple-therapy arms, several secondary outcomes, and reported comparisons for selected endpoints. It does not report a multiplicity adjustment, a testing hierarchy, or a prespecified family of comparisons. The posted p-values are unadjusted. Consequently, they describe individual comparisons without accounting for the possibility of multiple opportunities to observe a nominally unusual result.

General statistical context: multiplicity matters when many hypotheses are tested because the overall chance of at least one false-positive finding can rise. Common approaches include adjusting thresholds or specifying a primary comparison hierarchy in advance, but the registry record does not state that either was used. The primary results should therefore be distinguished from the broader collection of secondary outcomes and comparisons.

The registry record defines the primary analysis population as randomized participants with a baseline and at least one on- or post-treatment HCV RNA assessment. It does not describe the number or characteristics of randomized participants who lacked such measurements, how missing values were handled, whether participants were excluded from particular endpoint analyses, or whether sensitivity analyses were performed. Missing-data assumptions and their potential influence are therefore not assessable from the registry record.

For secondary outcomes, analyzed denominators differ across arms in the posted summaries. The registry record does not explain the reasons for those differences or state whether the same analysis population was used for every outcome. The specific handling of missing response assessments is not reported in the registry record. This limits direct comparisons across endpoints and prevents a full assessment of attrition-related bias.

The record also does not report a detailed statistical analysis plan, including model specifications, covariate adjustment, interim analyses, or the original sample-size justification. No interim analyses or statistical plan should be inferred from their absence in the registry record. The stated intent-to-treat population label does not fill in these missing details; its operational definition is the one given for the RNA endpoint.

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: acute pyelonephritis (9.1%).

The serious adverse event summaries report zero serious events in Treatment Arms A, B, D, and E among their listed at-risk groups. Treatment Arm C reports 1 serious event among 11 participants at risk. The registry record lists Acute Pyelonephritis at 9.1% among the top serious adverse event terms. It does not provide enough detail in the available summary to establish a broader pattern from that term alone.

Other adverse events are reported for all participants at risk in each of the five arms: 10 of 10 in Arm A, 9 of 9 in Arm B, 11 of 11 in Arm C, 10 of 10 in Arm D, and 10 of 10 in Arm E. These are group-level counts, not severity grades or evidence that every event was caused by study treatment. The registry record does not report the detailed event listings, exposure-adjusted rates, or a causal assessment in the available safety summary.

Deaths are not reported in the registry record. Safety counts from this small, open-label study are descriptive and do not establish comparative safety between regimens. Differences in exposure, follow-up, event definitions, and chance can affect such comparisons; relevant detail beyond the listed counts is not reported in the registry record.

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

The posted primary result describes how mean plasma HCV RNA changed from baseline to Day 29 in three Debio 025 triple-therapy regimens. The mean changes were more negative in Treatment Arms D and E than in Treatment Arm A, and the unadjusted pairwise intervals exclude zero. The estimates are short-term, on a log10 scale, and based on 10.0 participants in each primary arm.

This result does not establish the size of a lasting treatment effect. The primary endpoint is not a sustained viral response, and the registry record’s listed sustained-response outcome does not have a numerical result in the available outcome summaries. The observed Day 29 change cannot be used as a substitute for later outcome data that are not reported.

The result also does not establish that a regimen is superior overall, safe for a particular individual, or appropriate for a treatment decision. No medical advice follows from these group summaries. The randomized design enables comparisons between assigned arms, but the open-label structure, small groups, unadjusted testing, and unreported analysis details constrain how broadly the estimates can be interpreted.

Nor does the primary comparison answer how Debio 025 performs against no Debio 025 or placebo: the primary comparison is between the listed active regimens, with Arm A as the reference. The study included regimens that varied dose and combinations during the initial period, so a contrast between arms reflects the regimen difference as assigned, not an isolated effect of one component under all circumstances.

The appropriate interpretation is therefore narrow: these data describe observed differences in a specified early RNA endpoint in chronic HCV genotype 1 patients who were nonresponders to standard treatment. The confidence intervals show uncertainty in the magnitude, and missing later-outcome results mean the registry record does not establish whether the early differences correspond to response at the end of treatment or after follow-up.

17. Why This Trial Matters Statistically

Statistically, this trial illustrates the distinction between a biological measurement taken early in treatment and an outcome measured after treatment. The primary endpoint is continuous and captures mean change in HCV RNA over baseline to Day 29. Later response endpoints are categorical percentages assessed at different time points. Their statistical summaries answer related but nonidentical questions, and a pattern in one cannot be assumed to carry over to another.

The multi-arm design makes treatment-regimen contrasts possible while varying Debio 025 dosing and the combination during the initial treatment period. That design also creates multiple comparisons. The registry record provides unadjusted comparisons for selected outcomes but does not report a multiplicity strategy, highlighting why a nominal p-value should be interpreted in the context of the full set of outcomes and planned analyses.

The study is also a useful example of why effect estimates need precision information. The reported mean differences are accompanied by confidence intervals, making uncertainty visible rather than relying on p-values alone. The small arm sizes make that uncertainty important. The estimates can describe the observed data, but they do not eliminate uncertainty about the true magnitude or later outcomes.

Finally, the distinction between a study’s original design and retrospective planning illustrations matters. The sample-size figures based on observed effects are hypothetical planning tools under stated assumptions, not evidence of the trial’s original power or design rationale. The registry record does not report the original sample-size justification. Keeping those claims separate helps avoid treating a planning calculation as a finding from the completed trial.

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.

The primary comparisons involve small groups, with 10.0 participants in each of the three reported primary arms. This limits precision and makes the observed mean changes and standardized contrasts potentially sensitive to individual observations. The registry record does not provide participant-level data or distributions that would allow a fuller assessment of outliers or shape of the outcome.

The study is open-label and has no masking. The registry record does not report the allocation concealment procedure, adherence, treatment discontinuations, or how changes in assigned treatment were addressed. These details matter for understanding how closely observed outcomes correspond to assigned regimens.

The primary outcome is measured at Day 29, while subsequent treatment continued for substantially longer in the described regimens. Numerical results for several listed later outcomes, including sustained viral response, are not reported in the registry record. Thus, the available primary result cannot answer questions about durability. The available safety summary is also limited: deaths are not reported, and detailed adverse-event descriptions and causal assessments are not reported in the registry record.

There are multiple arms, endpoints, and selected comparisons, but no multiplicity approach or comprehensive analysis plan is reported. Missing-data procedures, reasons for differing secondary denominators, and sensitivity analyses are also not reported in the registry record. These omissions constrain assessment of potential selection, missingness, and analysis-choice effects.

Finally, the study concerns chronic HCV genotype 1 patients who did not respond to standard treatment. The registry record does not establish that the findings apply to other genotypes, other treatment histories, or other populations. The generalizability of the observed short-term RNA differences is therefore limited to the population and regimens described.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of Debio 025 in Combination With PegIFN Alpha-2a and Ribavirin in Chronic HCV Patients Non-responders to Standard Treatment — NCT00537407.
• Registry record last updated 2016-02-17; status last verified 2016-02.
• Results first posted 2015-05-07.
• 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

NCT00537407 is a completed, randomized, open-label, parallel-group phase 2 study sponsored by Debiopharm International SA. It enrolled 50 participants with chronic HCV genotype 1 who were nonresponders to standard peginterferon alpha and ribavirin treatment. Five treatment arms evaluated different Debio 025 regimens with peginterferon alpha-2a and ribavirin.

The primary endpoint was mean change in plasma HCV RNA from baseline to Day 29 in triple-therapy Arms A, D, and E. The posted arm-level means were -0.881, -2.321, and -2.02 log10(IU/mL), respectively. Unadjusted comparisons versus Arm A were reported for Arms D and E, with confidence intervals excluding zero. These are short-term findings with limited precision, and they do not establish later response.

The record also includes secondary outcome summaries and safety counts, but numerical results for some listed outcomes are not reported in the registry record. Multiplicity handling, missing-data methods, detailed statistical plans, and the original sample-size rationale are not reported in the registry record. The findings should be interpreted as specific to the study population, regimens, and reported outcomes.