A Safety and Effectiveness Study of TMC435 in Chronic, Genotype 1, Hepatitis C Patients Who Failed to Previous Standard Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Effectiveness Study of TMC435 in Chronic, Genotype 1, Hepatitis C Patients Who Failed to Previous Standard Treatment (NCT00980330), a randomized phase 2 study. The primary outcome is The Percentage of Participants Achieving a Sustained Virologic Response at the End of Treatment (EOT) and 24 Weeks After the EOT (SVR24).

2. Clinical Question

These details frame the question as a comparison of several doses and treatment durations, not a single TMC435 regimen against placebo. The groups also received the same named background medicines, while placebo was used in place of TMC435 in the comparator group. The registry record describes a randomized, double-blind, placebo-controlled trial. The outcome is a virologic measure at a specified follow-up time; it does not by itself describe every aspect of participants’ health or experience.

3. Trial Design

The record describes a Phase IIb randomized, double-blind, placebo-controlled trial with quadruple masking and a parallel-group design. It lists an enrollment of 463 and a completed status. Participants were allocated across six TMC435 regimens and a placebo-plus-standard-treatment group. The registry record gives arm-level outcome denominators ranging from 65 to 68, which need not be identical to the enrollment figure because the primary population definition concerns participants who received at least 1 dose.

TMC435 was given once daily at either 100 mg or 150 mg for 12, 24, or 48 weeks. Peg-IFN-alfa-2a and ribavirin were included in every regimen, for a planned 48-week course. In the shorter TMC435 regimens, placebo was used after the active TMC435 period alongside the background medicines. The comparator received placebo and the background medicines throughout the stated 48-week course.

Randomization is intended to create comparable groups on average, while masking is intended to limit the influence of treatment knowledge on care, reporting, and assessment. Those are general design principles; the registry record does not describe how randomization or masking was implemented in practice. It also does not report the method of sequence generation, allocation concealment, or whether masking was maintained throughout the trial.

The record gives the study start as 2009-10 and primary completion as 2011-08. The listed primary endpoint is assessed at Week 72. Further details about the protocol, the original sample-size justification, interim analyses, and the prespecified statistical plan are not reported in the registry record. The posted comparisons therefore should be read with the limitations of the available analysis information in mind.

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: A total of 618 participants were screened. Of these, 463 participants were randomized of whom 462 participants started treatment. One participant in the placebo group was 'randomized in error,' did not receive treatment, and was withdrawn from the study due to non-compliance (did not come for visit).

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat: Participants who received at least 1 dose of study medication were included.

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.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Percentage of Participants Achieving a Sustained Virologic Response at the End of Treatment (EOT) and 24 Weeks After the EOT (SVR24), measured over Week 72.

The primary endpoint is the percentage of participants achieving a sustained virologic response 24 weeks after the end of treatment, called SVR24. The registry definition requires plasma HCV RNA to be below 25 IU/mL and undetectable at the end of treatment and 24 weeks after treatment ends. The stated timeframe is Week 72. The primary population is intent-to-treat as defined in the record: participants who received at least 1 dose of study medication were included.

This endpoint captures whether the specified virologic status was present at the treatment-end assessment and remained present at the later follow-up assessment. Using a post-treatment assessment distinguishes a response observed only during treatment from a response that is still observed after the treatment course has ended. This is a general reason that sustained-response outcomes are used in trials evaluating antiviral regimens; it does not establish that every participant had the same clinical course or experience.

The outcome is reported as a percentage, so its meaning is the proportion of the analyzed group meeting the endpoint definition. The registry record does not provide confidence intervals for the arm-specific percentages. It does provide recalculated unadjusted comparisons between each TMC435 group and the placebo group, with confidence intervals for the risk differences. Those comparisons address the difference between groups, while the endpoint percentages describe each group separately.

7. Results Posted in the Registry

• TMC435 100mg 12 Wks + PR48: 69.7% (46/66) versus 22.7% (15/66) on control; risk difference 47.0 percentage points (95% CI 32.0 to 62.0), risk ratio 3.07 (1.91–4.92); unadjusted two-proportion z-test p = <0.001.
• TMC435 100mg 24 Wks + PR48: 66.2% (43/65) versus 22.7% (15/66) on control; risk difference 43.4 percentage points (95% CI 28.1 to 58.7), risk ratio 2.91 (1.81–4.69); unadjusted two-proportion z-test p = <0.001.
• TMC435 100mg 48 Wks + PR48: 60.6% (40/66) versus 22.7% (15/66) on control; risk difference 37.9 percentage points (95% CI 22.3 to 53.4), risk ratio 2.67 (1.64–4.33); unadjusted two-proportion z-test p = <0.001.
• TMC435 150mg 12 Wks + PR48: 66.7% (44/66) versus 22.7% (15/66) on control; risk difference 43.9 percentage points (95% CI 28.7 to 59.2), risk ratio 2.93 (1.82–4.72); 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 Rapid Virologic Response (RVR)

• 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:
  • TMC435 100mg 12 Wks + PR48: 66.7% (44/66) versus 1.5% (1/66) on control; risk difference 65.2 percentage points (95% CI 53.4 to 76.9), risk ratio 44.00 (6.24–310.04); unadjusted two-proportion z-test p = <0.001.
  • TMC435 100mg 24 Wks + PR48: 58.5% (38/65) versus 1.5% (1/66) on control; risk difference 56.9 percentage points (95% CI 44.6 to 69.3), risk ratio 38.58 (5.46–272.78); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 12 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 24 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Percentage of Participants Achieving an Early Virologic Response (EVR)

• 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:
  • TMC435 100mg 12 Wks + PR48: 90.9% (60/66) versus 60.6% (40/66) on control; risk difference 30.3 percentage points (95% CI 16.6 to 44.0), risk ratio 1.50 (1.22–1.85); unadjusted two-proportion z-test p = <0.001.
  • TMC435 100mg 24 Wks + PR48: 87.7% (57/65) versus 60.6% (40/66) on control; risk difference 27.1 percentage points (95% CI 12.8 to 41.3), risk ratio 1.45 (1.17–1.79); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 12 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 24 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The Percentage of Participants Achieving a Complete Early Virologic Response (cEVR)

• 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:
  • TMC435 100mg 12 Wks + PR48: 81.8% (54/66) versus 19.7% (13/66) on control; risk difference 62.1 percentage points (95% CI 48.8 to 75.5), risk ratio 4.15 (2.52–6.85); unadjusted two-proportion z-test p = <0.001.
  • TMC435 100mg 24 Wks + PR48: 73.8% (48/65) versus 19.7% (13/66) on control; risk difference 54.1 percentage points (95% CI 39.8 to 68.5), risk ratio 3.75 (2.26–6.23); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 12 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for TMC435 100mg 24 Wks + PR48 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The numerical secondary results posted for rapid virologic response, early virologic response, and complete early virologic response follow a broadly similar direction: the TMC435 groups have higher observed percentages than the placebo-plus-standard-treatment group for these measures. These are earlier response assessments than the primary SVR24 outcome. They provide context about responses during treatment, while SVR24 asks whether the specified status is present after the course of treatment and follow-up.

The secondary outcomes are related to the primary question because they measure other aspects or timings of virologic response. They are not substitutes for the primary endpoint. A pattern in an early response outcome does not by itself establish the later sustained outcome, and a result at one follow-up time does not answer every question about response over time. The registry record also lists other secondary outcomes, including measures of HCV RNA levels, SVR12, and viral breakthrough; numerical results for those other outcomes are not reported in the registry record.

Unadjusted secondary results carry less weight as confirmatory evidence when many outcomes and comparisons are examined. In general, testing multiple hypotheses increases the chance of finding at least one apparently notable result by chance if no adjustment or prespecified hierarchy is used. The record does not report a multiplicity strategy or a confirmatory testing hierarchy. The posted secondary comparisons should therefore be treated as exploratory context rather than as independent confirmation of the primary finding.

The registry record lists no reported analyses for these secondary results. Their posted comparisons are unadjusted recalculations, and the record does not describe adjustments for baseline factors or missing results. The interpretation is consequently limited to the observed percentages and the listed simple comparisons, without assuming that all secondary hypotheses were prespecified or controlled as a family.

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

• The Percentage of Participants With a Greater Than 2 log10 Drop in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Time Points During Treatment
• The Percentage of Participants Achieving Plasma Levels of Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Undetectable During Treatment and Follow-up
• The Percentage of Participants Achieving Plasma Levels of Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) <25 IU/mL Detectable or Undetectable During Treatment and Follow-up
• The Percentage of Participants Achieving a Rapid Virologic Response (RVR)
• The Percentage of Participants Achieving an Early Virologic Response (EVR)
• The Percentage of Participants Achieving a Complete Early Virologic Response (cEVR)
• The Percentage of Participants Achieving a Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12)
• The Percentage of Participants With Viral Breakthrough

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either met the stated SVR24 definition or did not. The reported arm results are percentages, which express the share of participants in each group meeting the endpoint. The primary population definition includes participants who received at least 1 dose of study medication. This is the registry’s stated intent-to-treat definition; the record does not provide further detail about how missing endpoint values were handled.

What does a risk difference describe?

A risk difference compares the proportions with the outcome in two groups by subtracting one group’s proportion from the other. It is expressed on the proportion scale in the posted recalculations. A positive value in these comparisons means the observed proportion meeting SVR24 was higher in the TMC435 group than in the placebo group. Unlike a relative measure, a risk difference describes the absolute separation between the two proportions on that scale. The estimates in this record are unadjusted calculations from the posted group summaries.

What does a confidence interval add?

A confidence interval gives a range of values compatible with the observed data under the statistical method used. It communicates uncertainty about the estimated group difference rather than merely stating which direction the point estimate takes. A wider interval means the estimate is less precise; an interval that does not include the no-difference value is inconsistent with that value at the corresponding confidence level under the method’s assumptions. The registry record does not identify the confidence level or detailed method for the recalculated intervals, so those details should not be inferred.

How should the p-values be read?

The listed p-values are unadjusted, and each is reported as <0.001. In general, a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true, nor does it measure clinical importance. Because the results are unadjusted, the p-values do not account for the multiple TMC435 regimens and endpoint comparisons considered in the trial record.

What does randomization contribute?

In general, randomized allocation supports comparisons by reducing systematic differences in baseline characteristics on average. It does not guarantee exact balance in every observed or unobserved characteristic, especially within individual groups. The record confirms randomization but does not report baseline characteristics in the data or give details about the randomization procedure. The comparisons should therefore be understood as comparisons of observed trial groups, interpreted in light of the design information actually reported.

What is not established by the posted analysis?

The registry record lists no reported analyses for the primary or posted secondary comparisons. That makes it important to distinguish the unadjusted recalculations from the trial’s original inferential plan. Details of covariate adjustment, missing-data methods, multiplicity control, subgroup analyses, and interim analyses are not reported in the registry record. The absence of those details does not establish that a particular method was or was not used outside the posted record.

The group percentages are based on the stated denominators, but endpoint counts may be affected by participant-level outcome availability and the endpoint definition. The record provides counts for successes in the recalculated primary comparisons, but it does not explain the handling of missing outcome data. No adjustment for differences among participants is represented in the simple risk-difference calculations. These points limit how far the comparisons can be interpreted beyond the groups and outcomes recorded.

The secondary outcomes include other binary virologic measures and responses at different time points. Each outcome has its own definition and timing, so a result on one measure should not be treated as interchangeable with SVR24. General statistical practice treats outcomes other than the designated primary endpoint cautiously, especially when multiple comparisons are examined without a reported multiplicity strategy. The registry record does not provide a multiplicity plan.

11. Confidence Intervals and Precision

The posted primary percentages describe each group, while the recalculated confidence intervals describe the risk difference between a TMC435 group and the placebo-plus-PR48 group. The intervals are useful because a point estimate alone gives no direct indication of how uncertain the estimated difference is. For the 100 mg, 12-week regimen, the risk difference is 0.470 with a confidence interval from 0.320 to 0.620. For the 150 mg, 48-week regimen, it is 0.573 with an interval from 0.432 to 0.713. These are examples of the range estimates reported for the comparisons.

All six recalculated primary confidence intervals lie above the no-difference value, consistent with the direction of the corresponding positive point estimates. Their lower and upper bounds still span a range of possible group differences, so the exact magnitude is uncertain. The interval is not a range containing a specified percentage of individual participant outcomes. It describes uncertainty in the estimated comparison under the calculation method.

Precision depends in part on the amount of information in the groups and on the observed data. The primary arm denominators range from 65.0 to 68.0, and the comparison intervals are not identical in width. These modest group sizes and the range of compatible effects are relevant when considering how precisely the size of the difference has been estimated. The record does not report confidence intervals for the primary arm percentages themselves, nor does it identify the confidence level or full interval method used for the recalculations.

Precision is distinct from statistical significance. The unadjusted p-values are all reported as <0.001, while the intervals show that the estimated magnitude remains uncertain. Neither measure alone determines the clinical importance of an outcome difference. The comparisons also remain unadjusted for the multiple regimens examined.

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 group differences, not the original design calculations for this trial. For these binary outcomes, the figures are participants per arm, not total events. The planning 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 a 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 participants per arm for a design that would have an 80% chance of detecting the assumed effect under the listed planning assumptions, if that effect and those assumptions held. The 90% power column gives the corresponding illustration for a higher probability of detection. These are design-planning quantities, not guarantees that a future study will detect an effect. The figures should be read for the specific comparison and effect fraction associated with each row, rather than transferred to another endpoint or population.

Rows that plan for 100% of the observed effect use the full observed difference as the assumed target. Rows planning for 75% or 50% of the observed effect use smaller target effects. Smaller effects generally require more participants to detect with the same power and significance level; this is reflected in the listed planning figures. Since observed effects can be unstable, especially in modest-sized groups, using them as planning assumptions may not yield a reliable estimate of the sample size needed for a future trial.

These figures are not observed power. Observed power is not a useful substitute for reading the estimate and its uncertainty after results are available. Here, the planning values illustrate how assumptions about the target effect and desired power influence sample size; they do not explain the trial’s actual enrollment decision.

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 = 0.227; treatment proportion p₁ = 0.697; average p̄ = 0.462.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7051 = 1.3819.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6220 = 0.5234.
4. n = (1.3819 + 0.5234)² / (0.4697)² = 16.5, rounded up to 17 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 <- 0.227272727272727                          # control proportion
p1 <- 0.696969696969697                          # 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(980330)
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 = 17 (80% power), 22 (90% power)
 75% of observed effect: n per arm = 30 (80% power), 39 (90% power)
 50% of observed effect: n per arm = 64 (80% power), 84 (90% power)
power.prop.test: 16.5 
Simulated power at n = 17 per arm: 0.834 (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 trial includes multiple TMC435 regimens, a placebo comparator, a primary endpoint, and numerous secondary outcomes. When many comparisons are considered, the chance of at least one apparently unusual result can increase. A statistical plan may address this through a prespecified hierarchy, an adjustment to significance thresholds, or another multiplicity strategy. Such a strategy is not reported in the registry record. The displayed p-values are explicitly unadjusted, so they should not be read as controlling the error rate across all comparisons in the trial.

The registry record lists no reported analyses. It therefore does not establish whether the posted comparisons match the original analysis plan, whether other analyses were conducted, or whether an adjustment was made elsewhere. Details of any planned interim analyses, subgroup analyses, covariate adjustment, or sensitivity analyses are not reported in the registry record. These omissions limit assessment of whether the results were analyzed and presented according to a prespecified plan.

The primary population is defined as participants who received at least 1 dose of study medication. The record does not explain how participants with missing SVR24 measurements were handled, whether any were treated as nonresponders, or whether an alternative imputation or sensitivity method was used. It also does not report the extent or reasons for missing outcome data. Missingness can matter because the observed percentage may not represent the full randomized group if outcome availability is related to participants’ status or treatment experience. This is a general concern, not a claim that missingness occurred in a particular way in this trial.

Other features relevant to interpreting the comparisons, including baseline balance, protocol deviations, and the method used to preserve masking, are not detailed in the results information. The record’s description of randomization and masking is informative, but does not answer these implementation questions. Without the original statistical plan and fuller analysis details, the recalculated comparisons are best viewed as descriptive, unadjusted evidence rather than a complete account of the trial’s confirmatory 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: urinary tract infection (3.1%), cellulitis (1.5%), clostridium difficile colitis (1.5%), pancytopenia (1.5%), vomiting (1.5%).

The registry record reports serious adverse event counts by treatment group. The counts affected are 3 of 66 for TMC435 100 mg for 12 weeks, 5 of 65 for 100 mg for 24 weeks, and 3 of 66 for 100 mg for 48 weeks. For the 150 mg regimens, the counts are 7 of 66 for 12 weeks, 5 of 68 for 24 weeks, and 8 of 65 for 48 weeks. The placebo 48-week group has 4 of 66 participants with a serious adverse event. These are group-specific counts and denominators, not comparative estimates adjusted for other factors.

The most frequently listed serious adverse event terms are urinary tract infection at 3.1%, and cellulitis, Clostridium difficile colitis, pancytopenia, vomiting, and abdominal pain at 1.5% each. The record does not specify the treatment group for these listed terms in the information described. The death counts are not reported in the registry record.

These safety figures describe reported events in the trial groups; they do not establish that an event was caused by a particular study medicine. The registry record does not provide further details on event timing, severity beyond the serious classification, exposure duration, or comparative statistical analyses. The counts should be interpreted descriptively and alongside the study’s design and reporting limitations.

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

The primary results describe the observed percentages meeting the registry’s SVR24 definition in each trial group. The percentages were higher in each of the six TMC435 groups than in the placebo-plus-PR48 group, and the recalculated unadjusted risk differences were positive, with listed unadjusted p-values of <0.001. This is a description of the posted trial data, not a recommendation about treatment or a conclusion about what any individual participant would experience.

The primary endpoint is specific: undetectable HCV RNA below 25 IU/mL at the end of treatment and 24 weeks after treatment ended. It does not represent every possible clinical outcome, adverse effect, quality-of-life measure, or longer-term outcome. The record reports the assessment at Week 72 but does not provide numerical results for every outcome listed in the registry. Its results therefore answer the specified endpoint question more directly than broader questions about health or treatment experience.

These findings apply to the trial population described: people with chronic genotype 1 hepatitis C who had failed previous standard treatment with pegylated interferon and ribavirin. They should not automatically be generalized to people with other genotypes, treatment histories, or clinical characteristics. The trial compared several TMC435 schedules with a placebo regimen on a specific background of pegylated interferon and ribavirin; the comparisons do not isolate the effect of TMC435 from every other aspect of that treatment context.

The risk differences are unadjusted recalculations, and the registry record does not report an analysis plan, multiplicity adjustment, missing-data method, or the trial’s original sample-size rationale. Those limitations affect the strength and scope of the statistical interpretation. Statistical evidence from these group comparisons is not the same as evidence of clinical importance, and the registry record alone does not establish how the observed results should inform an individual decision.

17. Why This Trial Matters Statistically

This trial is statistically informative because it compares several TMC435 dose-and-duration regimens with the same placebo-plus-standard-treatment group. The multiple arms allow the observed primary percentages to be considered across different schedules, while the common comparator gives a reference for each posted comparison. The results also demonstrate why the arm-level percentages and comparative estimates answer related but distinct questions: a percentage describes one group, whereas a risk difference contrasts two groups.

The primary endpoint is assessed after the treatment course, rather than only during treatment. That distinction matters for interpretation because an early virologic measure and a sustained follow-up measure capture different time points. The posted secondary findings offer additional context, but their status as unadjusted comparisons means they should not be treated as multiple independent confirmations.

The record also illustrates the importance of reporting analysis details. Randomization, masking, and the endpoint definition are specified, but the original analysis plan, missing-data methods, multiplicity approach, and design assumptions are not reported in the registry record. Without these details, readers can describe the observed pattern and its unadjusted precision, but cannot fully assess how the posted comparisons relate to prespecified inferential goals.

Finally, the observed group differences should be separated from their precision and from their clinical meaning. The confidence intervals make uncertainty in the estimated differences visible; the p-values address a narrower statistical question. Neither resolves the questions left open by absent analysis details or establishes how broadly the results apply beyond this trial population and treatment context.

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 results concern a specific population: participants with chronic genotype 1 hepatitis C who had failed previous pegylated interferon and ribavirin treatment. The record does not support direct extension to different hepatitis C genotypes, treatment histories, or populations not described in the trial. The tested regimens all included pegylated interferon and ribavirin, so the comparisons are tied to that background treatment context.

The record describes a Phase IIb trial and reports group-level results for six TMC435 schedules and a placebo schedule. It does not report direct comparative analyses between the TMC435 regimens, so apparent differences among their percentages should not be treated as established differences between those regimens. The posted risk-difference comparisons are against the placebo group and are unadjusted recalculations.

The registry record does not report the trial’s original sample-size assumptions, the method for handling missing outcome measurements, a multiplicity plan, or whether interim analyses were conducted. It lists no reported analyses. The confidence level and full method for the recalculated intervals are also not specified in the record described. These gaps constrain assessment of the precision, confirmatory status, and robustness of the comparisons.

The primary endpoint is a defined virologic outcome at a stated follow-up time. It does not capture every clinical outcome or participant experience. For safety, the record provides serious adverse event counts and selected terms but does not report deaths, event timing, or detailed comparative analyses. These reporting limitations mean that the available safety information should be treated as descriptive rather than as a complete account of comparative safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Safety and Effectiveness Study of TMC435 in Chronic, Genotype 1, Hepatitis C Patients Who Failed to Previous Standard Treatment — NCT00980330.
• Registry record last updated 2014-06-09; status last verified 2014-05.
• Results first posted 2014-02-06.
• 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

NCT00980330 is a completed randomized, double-blind, placebo-controlled Phase IIb parallel-group trial with quadruple masking. The registry lists an enrollment of 463, a start of 2009-10, and primary completion in 2011-08. Participants had chronic genotype 1 hepatitis C and had failed previous standard treatment with pegylated interferon and ribavirin.

The study compared six TMC435 schedules, combining 100 mg or 150 mg once daily for 12, 24, or 48 weeks with pegylated interferon alfa-2a and ribavirin, against placebo with the same background medicines. The primary outcome was SVR24 at Week 72. The posted percentages were higher in each TMC435 group than in the placebo group. Recalculated primary risk-difference comparisons were unadjusted, and each listed p-value was <0.001.

The record also posts secondary virologic results and serious adverse event counts. The trial’s original sample-size rationale, multiplicity strategy, missing-data methods, and full statistical analysis plan are not reported in the registry record. The posted comparisons therefore support a descriptive reading but do not provide a complete account of the trial’s prespecified statistical analysis.