An Efficacy, Safety, and Tolerability Study of TMC435 in Treatment-naive, Genotype 1 Hepatitis C-infected Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Efficacy, Safety, and Tolerability Study of TMC435 in Treatment-naive, Genotype 1 Hepatitis C-infected Participants (NCT01290679), a randomized phase 3 study. The primary outcome is The Percentage of Participants Achieving a Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12).

2. Clinical Question

The clinical question is about the response associated with adding TMC435 to a peginterferon-and-ribavirin regimen, compared with adding placebo to that background regimen. It is not a comparison of TMC435 alone with no treatment: both groups received active background medicines.

The timing of the primary outcome depends on the planned treatment duration. The registry gives the primary endpoint timeframe as Week 36 or Week 60, corresponding to the planned end of treatment followed by the SVR12 assessment. The response criterion is virologic: hepatitis C virus RNA must be undetectable in plasma at the specified follow-up.

The record describes this as a treatment-naive population, so its findings are specific to participants who had not received hepatitis C treatment before the study. It does not establish what the same regimens would produce in other patient populations or under different treatment conditions.

3. Trial Design

The registry describes a phase 3, randomized, double-blind, placebo-controlled, parallel-group study. It also records triple masking; the registry record does not specify which roles were masked. The trial is listed as completed, with enrollment of 393. Its recorded start was 2011-03 and primary completion was 2013-02.

Participants were assigned to TMC435 or placebo while receiving peginterferon alfa-2a or alfa-2b and ribavirin. In the TMC435 group, the study drug was given once daily for 12 weeks, while the background regimen lasted 24 or 48 weeks. In the placebo group, placebo was given once daily for 12 weeks and the background medicines for 48 weeks. The arms therefore differ in the study capsule, and their described background-treatment durations are not identical across all participants.

The primary analysis population is defined in the registry as all participants who were randomized and received at least one dose of study medication. This definition should be kept in mind when interpreting the analysis: it is not simply an account of everyone randomized regardless of treatment initiation.

The primary outcome was the percentage achieving sustained virologic response 12 weeks after planned treatment completion, assessed at Week 36 or Week 60. The record also lists 33 secondary outcomes, including other SVR timepoints and measures of HCV RNA response. Enrollment, outcome definitions, group results and the registry's reported statistical test describe the study, but the original sample-size justification and fuller design details 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.

Before assignment: 393 participants were randomly allocated to the 2 treatment arms. 391 participants received at least 1 dose of study medication and were included in the intent-to-treat analysis set.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.

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 The Percentage of Participants Achieving a Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12), measured over Week 36 or Week 60.

The primary endpoint is the percentage of participants with undetectable plasma hepatitis C virus RNA 12 weeks after the planned end of treatment. The registry labels this outcome SVR12 and gives the assessment timeframe as Week 36 or Week 60. The two timepoints reflect the endpoint's timing relative to the planned end of treatment, rather than a single fixed study week for all participants.

This is a binary outcome: each participant either meets the stated virologic response criterion or does not. Reporting the percentage in each group gives an interpretable summary of how often that criterion was met. Comparing the groups addresses whether the response proportions differ under the two assigned regimens.

A sustained response is assessed after treatment has ended, rather than only while participants are taking study medicines. That makes follow-up timing integral to interpreting the result: the endpoint is not an immediate on-treatment RNA measurement. The registry also lists SVR4, SVR24 and SVRW72 as secondary outcomes, which examine response at other specified times.

The endpoint is a virologic measure. It does not, on its own, describe every aspect of participants' health, treatment experience, or longer-term outcomes. Nor does an observed difference in response percentages establish that the same result would occur in a different population or with a different treatment regimen.

7. Results Posted in the Registry

• PBO 12Wks PR48: 50.0% (67/134) versus 81.3% (209/257) on control; risk difference -31.3 percentage points (95% CI -41.0 to -21.6), risk ratio 0.61 (0.51–0.74); 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.

The Percentage of Participants Achieving a Sustained Virologic Response at Week 72 (SVRW72)

• 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:
  • PBO 12Wks PR48: 50.0% (67/134) versus 78.6% (202/257) on control; risk difference -28.6 percentage points (95% CI -38.4 to -18.8), risk ratio 0.64 (0.53–0.76); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for PBO 12Wks PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Percentage of Participants Who Achieved a Sustained Virologic Response 24 Weeks After the Planned End of Treatment (SVR24)

• 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:
  • PBO 12Wks PR48: 50.0% (67/134) versus 80.5% (207/257) on control; risk difference -30.5 percentage points (95% CI -40.3 to -20.8), risk ratio 0.62 (0.52–0.74); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for PBO 12Wks PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Percentage of Participants Who Achieved a Sustained Virologic Response 4 Weeks After the Planned End of Treatment (SVR4)

• 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:
  • PBO 12Wks PR48: 53.0% (71/134) versus 84.8% (218/257) on control; risk difference -31.8 percentage points (95% CI -41.4 to -22.3), risk ratio 0.62 (0.53–0.74); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for PBO 12Wks PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover other sustained-response timepoints, changes and actual values in HCV RNA, on-treatment response, rapid virologic response and early virologic response. Across the secondary SVR outcomes with posted group comparisons, the pattern is consistent with the primary result: the TMC435 group has higher reported response percentages than the placebo group. The registry also reports p < 0.001 for the listed SVRW72, SVR24 and SVR4 comparisons.

These outcomes complement the primary endpoint by examining virologic response at different times, including during treatment and after its planned completion. Their consistency can help describe whether the primary pattern is isolated to one assessment time or appears across related measures. However, they are related outcomes, not independent replications of the primary result. Their timing and definitions differ, and the registry lists many secondary measures.

Multiplicity arises when several outcomes or comparisons are tested. In general, conducting many tests increases the chance that some results appear statistically notable even when there is no underlying difference for those particular outcomes. The registry record does not report a multiplicity adjustment or a prespecified hierarchy for interpreting secondary outcomes. Therefore, the reported secondary p-values should carry less confirmatory weight than the primary analysis, and should be read as supportive or descriptive rather than treated as separate proof.

The overall secondary pattern is relevant context, but it does not remove uncertainty about the analysis choices, missing measurements or how these outcomes were selected and interpreted. The primary endpoint remains the central result for this trial; secondary findings add detail without changing the need to interpret the primary estimate and its precision carefully.

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

• The Percentage of Participants Achieving a Sustained Virologic Response at Week 72 (SVRW72)
• The Percentage of Participants Who Achieved a Sustained Virologic Response 24 Weeks After the Planned End of Treatment (SVR24)
• The Percentage of Participants Who Achieved a Sustained Virologic Response 4 Weeks After the Planned End of Treatment (SVR4)
• Change From Baseline in log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA)
• Actual Values of log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA)
• Percentage of Participants With On-treatment Virologic Response at All Time Points
• The Percentage of Participants Achieving a Rapid Virologic Response (RVR)
• The Percentage of Participants Achieving a Early Virologic Response (EVR)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary because the registry records whether each participant met the undetectable-RNA criterion at the specified follow-up. For a binary outcome, a proportion summarizes the share of participants with the event. The reported percentages make the group results easy to read, while a formal comparison estimates how far apart the groups are and quantifies uncertainty in that contrast.

What does the reported comparison estimate?

The registry reports a difference in proportions using the Cochran-Mantel-Haenszel method. The posted estimate is 32.2, with a 95% confidence interval from 23.3 to 41.2. The estimate is reported in the direction of the TMC435 group relative to placebo. The exact unit presentation follows the registry's reported result. A difference in proportions focuses on the absolute separation between response rates; it is not the same quantity as a relative risk or an odds ratio.

The simple recalculation uses the posted group counts and denominators without the sponsor's stratified method. It expresses the contrast as placebo minus TMC435, yielding -0.313 with a 95% confidence interval from -0.410 to -0.216 and p < 0.001. The negative sign reflects the chosen subtraction order, not a contradictory direction of the group percentages. Because the registry's own analysis uses a different method and its reported result takes precedence, the recalculation is best treated as a check on the broad pattern rather than a replacement estimate.

What does the p-value say?

The registry reports p < 0.001 for the primary comparison. In general, a p-value measures how incompatible the observed data are with a specified null model, assuming that model and the test's other assumptions hold. It is not the probability that the null hypothesis is true, the probability that the result occurred by chance, or a measure of the size or clinical importance of the difference. The confidence interval provides complementary information by showing a range of estimates compatible with the data and method at the stated confidence level.

Why might the analysis method matter?

The Cochran-Mantel-Haenszel method is a method for comparing groups while accounting for strata. The registry does not report the particular stratification details in the record summarized for this analysis, so those details should not be inferred. An unadjusted comparison, by contrast, treats the posted group summaries as the basis for a direct calculation. When methods differ, their point estimates and intervals need not match exactly. The registry's own result remains the relevant reported inferential analysis.

Randomization is intended to make treatment groups comparable on average, including factors that may affect outcomes, but randomization does not guarantee perfect balance in any one trial. The registry identifies random allocation and parallel groups. It does not report all details needed to assess allocation procedures or analysis adjustments. The posted group percentages are therefore useful descriptive summaries, while interpretation of the formal comparison should follow the stated method and its limitations.

How should a percentage endpoint be distinguished from a count?

The response percentages describe the proportion meeting the endpoint, not the number of all possible outcomes across time. The reported primary group counts are 209 responses among 257 participants in the TMC435 group and 67 among 134 in the placebo group. Those counts underlie the displayed group proportions and the simple recalculation. They do not replace the registry's specified analysis population or answer how unobserved endpoint data were handled; missing-data handling is not reported in the registry record.

These methods describe statistical evidence for a group-level contrast. They do not establish a causal mechanism, account for unreported design choices, or turn the trial estimate into a guarantee about an individual participant's response. Interpretation should combine the estimate, its precision, the endpoint definition, the analysis population and the limits of the registry record.

11. Confidence Intervals and Precision

The sponsor's primary comparison has a 95% confidence interval from 23.3 to 41.2 around the reported difference of 32.2. A confidence interval is a measure of statistical precision: in general, it indicates the range of values reasonably compatible with the data and the analysis method at the stated confidence level. It is not a range containing a fixed proportion of individual participant outcomes, and it does not mean there is a 95% probability that this particular interval contains the true value.

The interval lies above zero, which is consistent with the reported direction of the group difference. Its width also matters: values across the interval represent a range of plausible magnitudes, rather than a single precisely known effect. The point estimate is the central summary, but it should be read together with this uncertainty range.

The simple unadjusted recalculation reports a 95% confidence interval from -0.410 to -0.216 for the placebo-minus-TMC435 risk difference. Its direction is reversed because the subtraction order differs from the sponsor's reported comparison. These estimates should not be treated as identical: the registry's reported method takes precedence, and the recalculation is unadjusted.

Precision depends in part on the amount of information in the analysis, including outcome counts and group sizes, as well as the analysis method. A confidence interval does not account for every possible source of uncertainty. In particular, it cannot resolve questions about missing-data handling, multiplicity, generalizability, or design details that are not reported in the registry record.

12. Planning a Similar Trial: Sample Size

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

The planning figures are illustrations based on the observed primary effect, not the trial's original design calculation. For this binary endpoint, the figures are participants per arm. They are not total event counts. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial's own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm under which a study would have an 80% chance of detecting the specified effect, if the calculation's assumptions hold. The 90% power column gives the corresponding number for a higher chance of detection. These are planning concepts, not guarantees: actual power depends on the true effect, design, data and analysis.

For planning for 100% of the observed effect, the primary-endpoint illustration lists 35 participants per arm for 80% power and 47 participants per arm for 90% power. For planning for 75% of the observed effect, it lists 60 participants per arm for 80% power and 79 participants per arm for 90% power. For planning for 50% of the observed effect, it lists 124 participants per arm for 80% power and 165 participants per arm for 90% power. The smaller-effect scenarios require more participants because a less pronounced separation between groups is harder to distinguish from random variation.

These calculated sample sizes are planning illustrations and are not observed power. Observed power is not a useful substitute for reading the estimate and its confidence interval after a trial has been completed.

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 = 0.813; treatment proportion p₁ = 0.500; average p̄ = 0.657.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6715 = 1.3162.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6339 = 0.5335.
4. n = (1.3162 + 0.5335)² / (-0.3132)² = 34.9, rounded up to 35 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 <- 0.813229571984436                          # control proportion
p1 <- 0.5                          # 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(1290679)
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 = 35 (80% power), 47 (90% power)
 75% of observed effect: n per arm = 60 (80% power), 79 (90% power)
 50% of observed effect: n per arm = 124 (80% power), 165 (90% power)
power.prop.test: 34.9 
Simulated power at n = 35 per arm: 0.811 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry's own primary analysis reports a Cochran-Mantel-Haenszel difference in proportions of 32.2, with a 95% confidence interval from 23.3 to 41.2 and p < 0.001. The simple recalculation uses the posted counts and is unadjusted. It gives a risk difference of -0.313 with a 95% confidence interval from -0.410 to -0.216, expressed as placebo minus TMC435.

The apparent sign difference reflects the comparison's orientation: the registry result is presented in the TMC435-over-placebo direction, while the recalculation subtracts the TMC435 proportion from the placebo proportion. The registry's estimated difference and interval also come from a different method, so exact agreement is not expected. The broad direction is consistent with the posted group proportions, which are higher in the TMC435 group.

The record does not flag a discrepancy between the posted results and recalculation. Even so, the sponsor's own reported analysis takes precedence for interpretation because it is the trial's stated inferential result. The recalculation is a transparent, unadjusted check and should not be used to replace that analysis or imply that unreported analytic details are known.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 33 secondary outcomes in addition to the primary endpoint. Testing multiple outcomes creates a multiplicity concern: in general, the more statistical comparisons made, the greater the chance that at least one appears notable by chance. A planned testing hierarchy or adjustment can help control that concern, but the record does not report a multiplicity strategy. It is therefore not possible to establish from the registry record whether the secondary analyses were intended as confirmatory, how their order was set, or whether any adjustment was used.

The primary comparison is reported with p < 0.001, but the presence of many outcomes still matters when interpreting the wider set of results. Statistical significance for individual secondary outcomes should not automatically be treated as independent confirmation. The outcomes are also related measures of virologic response, so they may share information rather than provide wholly separate tests of the treatment contrast.

The primary analysis population is defined as all participants randomized who received at least one dose of study medication. This is the population stated for all analyses in the record. It differs from a population defined solely by randomization, because participants who did not receive a dose are outside the registry's stated definition. The record does not provide further detail about the number or characteristics of any participants excluded under that definition.

Handling of missing endpoint data is not reported in the registry record. The record also does not say whether missing measurements were counted as failures, imputed, excluded from a particular analysis, or addressed through sensitivity analyses. Without those details, the influence of missing outcomes on the response percentages cannot be assessed from the record alone.

These omissions do not negate the posted results, but they constrain how completely they can be evaluated. A fuller interpretation would require the analysis plan and missing-data procedures, neither of which is reported in the registry record.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (0.8%), respiratory tract infection viral (0.7%), viral infection (0.7%), loss of consciousness (0.7%), neuropathy peripheral (0.7%).

The registry reports serious adverse events for 16 of 257 participants in the TMC435 group and 10 of 134 in the placebo group. It reports other adverse events affecting 243 of 257 participants in the TMC435 group and 131 of 134 in the placebo group. These are separate event categories as recorded; the figures should not be added together, since a participant may be represented in more than one category.

Among the serious adverse event terms listed, anaemia is reported as 0.8%. Respiratory tract infection viral, viral infection, loss of consciousness, peripheral neuropathy and thoracic outlet syndrome are each reported as 0.7%. The registry record does not establish from these figures whether an event was caused by a study medicine. The term percentages also do not provide a complete description of the seriousness, timing or clinical course of each event.

Deaths are not reported in the registry record. The adverse-event figures describe what the record posts for these groups; they are not, by themselves, a complete comparative safety analysis. Differences in follow-up, event definitions and attribution would require further information that is not reported in the registry record.

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

The primary result describes the proportion of participants in each assigned group who met the SVR12 criterion: undetectable plasma HCV RNA 12 weeks after the planned end of treatment. The posted proportions were higher in the TMC435 group than in the placebo group, and the registry's reported comparison gave a positive difference with a confidence interval above zero and p < 0.001.

This is evidence about the trial's regimens in its treatment-naive, genotype 1 hepatitis C population. It is not a comparison of TMC435 alone against no treatment, because both groups received peginterferon and ribavirin. It does not establish what response would occur for a particular individual or in people with different treatment histories, hepatitis C genotypes or treatment regimens.

The result also does not answer every question about benefit and harm. SVR12 is a virologic endpoint; it does not capture every health outcome or experience that may matter to participants. The adverse-event figures provide some safety information, but do not by themselves show causation or supply a complete assessment of risks.

Statistical significance should not be read as a guarantee of clinical importance, nor as proof that all uncertainty has disappeared. The confidence interval conveys uncertainty in the estimated group difference, while unreported details about missing data and multiplicity limit assessment of the broader evidence. The trial's findings are most appropriately understood as a group-level comparison under its recorded conditions and analysis, rather than as a universal conclusion about treatment.

18. Why This Trial Matters Statistically

This trial illustrates how a randomized comparison can address an addition to an existing regimen. Both groups received peginterferon and ribavirin, while TMC435 or placebo was assigned as the study capsule. That design frames the primary contrast as the incremental difference between the assigned study-drug strategies within the recorded background treatments.

It also shows why endpoint timing needs careful interpretation. SVR12 is defined relative to planned treatment completion, and the registry gives Week 36 or Week 60 as the assessment timeframe. The endpoint is not a single common calendar point for every planned treatment duration. Reading the definition and timeframe together prevents confusion between post-treatment response and on-treatment virologic measures.

The registry presents both group percentages and a sponsor-reported stratified comparison. An unadjusted recalculation can check the broad direction of the posted data, but the direction of a risk difference depends on which group is subtracted from which. Comparing estimates therefore requires attention to method, orientation and the analysis that the trial itself reports.

Finally, the record demonstrates the limits of registry-level interpretation. The primary estimate and confidence interval are informative, while multiplicity procedures, missing-data handling and the trial's original sample-size assumptions are not reported. Statistical reading involves recognizing both the strength of the posted comparison and the boundaries imposed by details unavailable in the record.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry's analysis population is defined as participants randomized who received at least one dose, rather than all randomized participants without qualification. The record does not provide further information about participants who may not have received a dose, or how their absence from the stated analysis population might affect interpretation.

Missing-data methods for SVR12 are not reported in the registry record. Without knowing how unobserved RNA results were handled, it is not possible to assess whether missing measurements could have influenced the response percentages or the group comparison. The record also does not report sensitivity analyses for alternative missing-data assumptions.

The trial lists many secondary outcomes, but a multiplicity strategy and hierarchy for interpreting them are not reported. This limits the confirmatory weight that can be assigned to secondary p-values. The reported primary result remains the central comparison, but the broader collection of analyses requires caution.

The original sample-size justification and design assumptions are not reported in the registry record. The planning illustrations are based on the observed effect and should not be mistaken for the trial's own prospective calculation. Further details of the Cochran-Mantel-Haenszel stratification are also not reported, limiting assessment of the sponsor's analysis choices.

The study's regimen details differ in planned background-treatment duration across the arm descriptions: TMC435 was paired with 24 or 48 weeks of background treatment, while the placebo description specifies 48 weeks. The record does not provide enough detail to explain how those durations were assigned. Generalizability is also bounded by the stated treatment-naive, genotype 1 population and the particular regimens studied.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: An Efficacy, Safety, and Tolerability Study of TMC435 in Treatment-naive, Genotype 1 Hepatitis C-infected Participants — NCT01290679.
• Registry record last updated 2014-06-13; status last verified 2014-06.
• Results first posted 2014-06-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

NCT01290679 is a completed phase 3 randomized, double-blind, placebo-controlled parallel-group trial sponsored by Janssen R&D Ireland. It enrolled 393 treatment-naive participants with genotype 1 hepatitis C. The trial compared TMC435 with placebo, each added to peginterferon alfa-2a or alfa-2b and ribavirin.

The primary endpoint was SVR12: undetectable plasma HCV RNA 12 weeks after planned treatment completion. The posted response percentages were 81.3% with TMC435 and 50.0% with placebo. The registry's Cochran-Mantel-Haenszel comparison reported a difference of 32.2, with a 95% confidence interval from 23.3 to 41.2 and p < 0.001. The registry's reported analysis takes precedence over the unadjusted recalculation.

Secondary outcomes include other sustained-response timepoints and virologic measures. The registry record does not report the original sample-size assumptions, multiplicity strategy or missing-data methods.