This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus (NCT01628692), a randomized phase 2 study. The primary outcome is Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01628692 |
| Phase | Phase 2 |
| Condition | Hepatitis C Virus |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 230 |
| Arms in the primary outcome | 6 |
| Lead sponsor | Bristol-Myers Squibb |
| Results posted | Yes |
2. Clinical Question
Population
Participants had genotype 1 chronic hepatitis C and were either treatment-naive or null responders to prior peginterferon alfa and ribavirin therapy. The primary outcome population included participants who were randomized and received at least 1 dose of active study therapy. The reported treatment groups distinguish genotype 1a or 1b and treatment-naive or null-responder status.
Intervention
The study assessed daclatasvir and simeprevir, with or without ribavirin. The posted groups include daclatasvir plus simeprevir without ribavirin for genotype 1b, and combinations including ribavirin for genotype 1b and genotype 1a. The record describes a 12-week course for the genotype 1b group without ribavirin; the complete ribavirin dosing descriptions are not reported in the registry record.
Comparator
The posted recalculated comparisons use the genotype 1b, treatment-naive group receiving daclatasvir plus simeprevir without ribavirin as the reference. Other groups differ not only in the regimen but also in genotype, prior treatment response, or both. These comparisons therefore describe differences between the posted groups; they should not automatically be read as isolated treatment effects.
Primary question
What percentage of participants in each group had sustained virologic response at post-treatment Week 12? The endpoint required hepatitis C virus RNA below the lower limit of quantitation at follow-up. The study also reported early virologic response measures and adverse-event information. The registry record does not report a posted analysis plan explaining how formal comparisons across the groups were intended to be made.
3. Trial Design
This was a Phase 2, randomized, open-label, parallel-group study sponsored by Bristol-Myers Squibb. The registry lists enrollment of 230 and a completed study. It records a start in 2012-07 and primary completion in 2013-08. Participants were assigned to treatment groups, but masking was none, so the study was not blinded.
The treatment groups were organized by hepatitis C genotype and prior treatment history. Genotype 1b groups included treatment-naive participants and null responders receiving daclatasvir plus simeprevir, with or without ribavirin. Genotype 1a groups received daclatasvir, simeprevir, and ribavirin, and were also divided by prior treatment history. The posted group sizes and outcomes are therefore not a simple set of like-for-like comparisons of regimens: genotype and treatment history vary across groups as well.
The primary outcome population was defined as participants who were randomized and received at least 1 dose of active study therapy. The registry record gives the endpoint definition and the population but does not report details such as how missing endpoint measurements were handled. A full description of the randomization procedure, allocation concealment, stratification, and the original statistical plan is not reported in the registry record.
SVR12 was assessed at post-treatment Week 12. The registry also lists early virologic response outcomes and safety measures. Numerical results are posted for several early virologic endpoints, while numerical results for some listed outcomes are not reported in the registry record. The design and results describe a clinical study; they do not by themselves establish that observed differences between groups are caused by a particular component of 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.
Before assignment: Of the 230 participants enrolled, 168 received treatment.
Overall Study
| Stage | Genotype 1b: Daclatasvir + Simeprevir (Naive) | Genotype 1b: Daclatasvir + Simeprevir (Null) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null) |
|---|---|---|---|---|---|---|
| STARTED | 53 | 23 | 51 | 20 | 12 | 9 |
| COMPLETED | 46 | 17 | 43 | 19 | 8 | 0 |
| NOT COMPLETED | 7 | 6 | 8 | 1 | 4 | 9 |
Reasons for not completing this period:
| Reason | Genotype 1b: Daclatasvir + Simeprevir (Naive) | Genotype 1b: Daclatasvir + Simeprevir (Null) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null) |
|---|---|---|---|---|---|---|
| Lack of Efficacy | 4 | 4 | 5 | 1 | 4 | 7 |
| Adverse Event | 2 | 0 | 2 | 0 | 0 | 0 |
| Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 |
| Death | 0 | 1 | 0 | 0 | 0 | 0 |
| Poor compliance/noncompliance | 1 | 0 | 0 | 0 | 0 | 0 |
| Administrative reason by sponsor | 0 | 0 | 0 | 0 | 0 | 1 |
| Completed 12 Week only | 0 | 0 | 0 | 0 | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: All participants who were randomized and received at least 1 dose of active study therapy (daclatasvir, simeprevir, ribavirin).
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: The analysis was performed on the treated participants defined as all randomized participants who received at least 1 dose of active study therapy.
Only the first 6 of 7 groups are shown.
| Characteristic | Unit | Genotype 1b: Daclatasvir + Simeprevir (Naive) | Genotype 1b: Daclatasvir + Simeprevir (Null) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) | Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null) |
|---|---|---|---|---|---|---|---|
| Participants analysed | 53 | 23 | 51 | 20 | 12 | 9 | |
| Age, Customized: <21 years | participants | 0 | 0 | 0 | 1 | 1 | 0 |
| Age, Customized: 21-<65 years | participants | 41 | 19 | 42 | 11 | 11 | 9 |
| Age, Customized: >=65 years | participants | 12 | 4 | 9 | 8 | 0 | 0 |
| Gender: Female | Participants | 31 | 11 | 26 | 11 | 5 | 2 |
| Gender: Male | Participants | 22 | 12 | 25 | 9 | 7 | 7 |
| Hepatitis C Virus RNA Distribution: <800,000 IU/mL | participants | 12 | 3 | 11 | 4 | 5 | 0 |
| Hepatitis C Virus RNA Distribution: ≥800,000 IU/mL | participants | 41 | 20 | 40 | 16 | 7 | 9 |
| Randomization Stratum: Hepatitis C Virus Genotype 1b | participants | 53 | 23 | 51 | 20 | 0 | 0 |
| Randomization Stratum: Hepatitis C Virus Genotype 1a | participants | 0 | 0 | 0 | 0 | 12 | 9 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12), measured over Post Treatment Week 12 (Follow-up period).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | 80% Confidence Interval |
| Unit | Percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint was the percentage of participants with sustained virologic response at post-treatment Week 12, abbreviated SVR12. The registry defined a response as hepatitis C virus RNA below the lower limit of quantitation at that follow-up point, whether the assay target was detected or not detected. RNA was measured by the Roche COBAS TaqMan HCV Test version 2.0 from the central laboratory.
SVR12 is a binary outcome: each participant either meets the stated response definition or does not. Reporting the percentage gives the proportion of the defined analysis population meeting the endpoint in each treatment group. The endpoint population included participants who were randomized and received at least 1 dose of active study therapy.
As a general statistical point, a post-treatment virologic endpoint is used to assess whether the specified laboratory response is present after the treatment period rather than only while treatment is being given. Its interpretation depends on the endpoint definition, timing, assay, and population used. The registry record reports those elements for SVR12, but it does not report all analysis details, including the handling of missing follow-up measurements. SVR12 is a laboratory endpoint; it should not be conflated with outcomes that the record does not measure or report.
7. Results Posted in the Registry
- Genotype 1b: Daclatasvir + Simeprevir (Null): 69.6% (16/23) versus 84.9% (45/53) on control; risk difference -15.3 percentage points (95% CI -36.5 to 5.8), risk ratio 0.82 (0.61–1.10); unadjusted two-proportion z-test p = 0.123.
- Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive): 74.5% (38/51) versus 84.9% (45/53) on control; risk difference -10.4 percentage points (95% CI -25.8 to 5.0), risk ratio 0.88 (0.72–1.07); unadjusted two-proportion z-test p = 0.187.
- Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null): 95.0% (19/20) versus 84.9% (45/53) on control; risk difference 10.1 percentage points (95% CI -3.5 to 23.7), risk ratio 1.12 (0.96–1.30); unadjusted two-proportion z-test p = 0.242.
- Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive): 66.7% (8/12) versus 84.9% (45/53) on control; risk difference -18.2 percentage points (95% CI -46.6 to 10.1), risk ratio 0.79 (0.52–1.19); unadjusted two-proportion z-test p = 0.141.
Risk difference: Genotype 1b: Daclatasvir + Simeprevir (Null)
95% CI: -36.5 to 5.8 percentage points
Recalculated from the posted summary statistics
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.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| Percentage of Participants With Rapid Virologic Response (RVR) at Week 4 | Binary Endpoint | Risk difference | -9.7 pts (-31.4 to 12.1) | 318 per arm |
| Percentage of Participants With Complete Early Virologic Response (cEVR) | Binary Endpoint | Risk difference | -11.0 pts (-31.4 to 9.4) | 212 per arm |
| Percentage of Participants With Extended Rapid Virologic Response (eRVR) | Binary Endpoint | Risk difference | -10.8 pts (-34.2 to 12.5) | 299 per arm |
Percentage of Participants With Rapid Virologic Response (RVR) at Week 4
- 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:
- Genotype 1b: Daclatasvir + Simeprevir (Null): 69.6% (16/23) versus 79.2% (42/53) on control; risk difference -9.7 percentage points (95% CI -31.4 to 12.1), risk ratio 0.88 (0.65–1.19); unadjusted two-proportion z-test p = 0.362.
- Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive): 68.6% (35/51) versus 79.2% (42/53) on control; risk difference -10.6 percentage points (95% CI -27.4 to 6.2), risk ratio 0.87 (0.69–1.09); unadjusted two-proportion z-test p = 0.217.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Genotype 1b: Daclatasvir + Simeprevir (Null) 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 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) and the control. The interval gives the range of effects that remain compatible with the data.
Percentage of Participants With 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:
- Genotype 1b: Daclatasvir + Simeprevir (Null): 73.9% (17/23) versus 84.9% (45/53) on control; risk difference -11.0 percentage points (95% CI -31.4 to 9.4), risk ratio 0.87 (0.67–1.14); unadjusted two-proportion z-test p = 0.256.
- Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive): 82.4% (42/51) versus 84.9% (45/53) on control; risk difference -2.6 percentage points (95% CI -16.8 to 11.7), risk ratio 0.97 (0.82–1.15); unadjusted two-proportion z-test p = 0.725.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Genotype 1b: Daclatasvir + Simeprevir (Null) 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 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) and the control. The interval gives the range of effects that remain compatible with the data.
Percentage of Participants With Extended Rapid Virologic Response (eRVR)
- 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:
- Genotype 1b: Daclatasvir + Simeprevir (Null): 60.9% (14/23) versus 71.7% (38/53) on control; risk difference -10.8 percentage points (95% CI -34.2 to 12.5), risk ratio 0.85 (0.59–1.23); unadjusted two-proportion z-test p = 0.351.
- Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive): 62.7% (32/51) versus 71.7% (38/53) on control; risk difference -9.0 percentage points (95% CI -26.9 to 9.0), risk ratio 0.88 (0.67–1.15); unadjusted two-proportion z-test p = 0.331.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Genotype 1b: Daclatasvir + Simeprevir (Null) 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 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) and the control. The interval gives the range of effects that remain compatible with the data.
The posted secondary virologic outcomes cover response at Week 4, complete early response at Week 12, and extended rapid response assessed at Week 4 and Week 12. Across these endpoints, the pattern is not uniform across groups: the relative ordering of the group percentages varies by endpoint and by treatment-history group. As with SVR12, group sizes differ, and the genotype 1a estimates are based on small groups. These outcomes add context about virologic response at earlier time points, but they do not replace the primary post-treatment endpoint.
Several outcomes listed in the registry, including end-of-treatment response, SVR12 by IL-28B gene categories, and serious adverse events and discontinuations due to adverse events and deaths, do not all have numerical results available in the posted secondary endpoint results. Numerical results for those outcomes are not reported in the registry record. Safety information is posted separately for serious and other adverse events.
As a general statistical principle, secondary outcomes may be useful for describing patterns and generating questions, but they usually carry less confirmatory weight than a prespecified primary endpoint. If many outcomes or contrasts are examined, the chance of seeing an apparently notable result by chance can increase. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes. The posted comparisons for the early virologic endpoints are unadjusted recalculations, so their p-values and intervals should not be treated as independent confirmation of the primary result.
The overall lesson is to assess early and sustained response measures as related but distinct outcomes. Their timing and definitions differ, and an early response does not itself establish the post-treatment SVR12 result. Without a reported plan for secondary analyses and multiplicity, the secondary findings are best treated as descriptive context rather than as a collection of definitive treatment comparisons.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- Percentage of Participants With Rapid Virologic Response (RVR) at Week 4
- Percentage of Participants With Complete Early Virologic Response (cEVR)
- Percentage of Participants With Extended Rapid Virologic Response (eRVR)
- Percentage of Participants With End of Treatment Response (EOTR)
- Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories
- Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died
9. Statistical Interpretation
The posted SVR12 percentages vary across the genotype and treatment-history groups. Among genotype 1b treatment-naive participants, the group receiving daclatasvir plus simeprevir without ribavirin had a reported response percentage of 84.9, while the corresponding group receiving ribavirin had 74.5. For genotype 1b null responders, the reported percentages were 69.6 without ribavirin and 95.0 with ribavirin. The genotype 1a groups receiving ribavirin had reported percentages of 66.7 among treatment-naive participants and 0.0 among null responders.
These are descriptive group results, not a clean comparison of ribavirin versus no ribavirin across otherwise identical populations. The no-ribavirin group in the posted comparisons is genotype 1b and treatment-naive, whereas other groups differ by genotype, treatment history, or both. The registry record does not report an adjusted analysis accounting for these differences. The small posted group sizes, especially for genotype 1a, also mean that the percentages should be read with their uncertainty in mind.
Unadjusted recalculations compare each listed group with the genotype 1b treatment-naive group receiving daclatasvir plus simeprevir without ribavirin. The recalculated risk-difference intervals include no difference for each comparison for which an interval is posted. The unadjusted p-values are 0.123, 0.187, 0.242, and 0.141 for the reported comparisons. These results do not establish a difference between groups; nor do they establish that groups are equivalent. The registry record reports no formal analyses, and these recalculations do not substitute for a sponsor analysis.
Interpretation should therefore focus on the observed percentages and the breadth of their uncertainty rather than treating the ordering of group estimates as a definitive ranking. Differences in genotype and prior response are central features of the group structure. The posted results support describing what was observed in these groups, but they do not isolate the contribution of ribavirin or establish a causal explanation for variation across groups.
10. Statistical Methods Explained
The primary outcome is binary: SVR12 was either present or absent under the registry definition. For a binary endpoint, a percentage is a way of expressing how often the event occurred within a group. The registry reports the percentage and an 80% confidence interval for each group. It also gives group sizes, allowing the reader to see that the estimates arise from groups of different sizes. The record does not report the original statistical analysis plan or the sponsor's inferential analyses.
What does a confidence interval express?
As a general statistical explanation, a confidence interval describes uncertainty in an estimated quantity under a specified method. A wider interval means that the estimate is less precise; a narrower interval means greater precision under that method. An 80% confidence interval is not the same as a 95% confidence interval. Its stated confidence level is part of how the interval should be interpreted, and it should not be silently treated as though a different confidence level had been used.
How should the group comparisons be read?
The comparisons use risk differences, which express the difference between the event proportions in two groups. A difference of zero corresponds to equal proportions. The reported estimates are unadjusted recalculations from the posted summary statistics, rather than adjusted model estimates. A recalculated interval that includes zero is compatible with no difference under that interval procedure; it may also be compatible with differences in either direction. It does not prove equality. The registry record reports no formal analyses, and no adjustment for multiple comparisons is reported.
The comparison groups are not interchangeable populations. The reference group is genotype 1b, treatment-naive, and received daclatasvir plus simeprevir without ribavirin. Other groups differ in genotype, prior treatment history, regimen, or a combination of these characteristics. Randomization is recorded for the study, but the registry record does not explain the allocation process in enough detail to determine how the posted group structure and contrasts relate to randomized comparisons. The posted recalculations should consequently be read as descriptive unadjusted contrasts, not as definitive estimates of a single treatment component's effect.
What can a p-value tell the reader?
As a general explanation, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be under the assumptions of a test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The unadjusted p-values in the recalculations are 0.123, 0.187, 0.242, and 0.141. They should be considered alongside the estimates, intervals, group sizes, and unadjusted nature of the comparisons. They are not reported sponsor analyses.
Why can small groups produce uncertain percentages?
As a general statistical point, percentages based on fewer observations can change substantially when the outcome status of a small number of participants changes. Their uncertainty is often reflected in wider intervals. That matters particularly for the genotype 1a groups and the null-responder group with a reported SVR12 of 0.0, for which no interval limits are posted. The missing interval limits are not reported in the registry record, so they should not be reconstructed from the displayed percentage.
What details are not available?
The registry record does not report the original sample-size justification, the statistical model or test used for the sponsor's planned analysis, the handling of missing outcome data, or whether interim analyses were conducted. It also does not report a multiplicity procedure. Those details cannot be inferred from the posted results. General principles can explain why such choices matter, but they do not establish which methods this study used.
The registry's primary endpoint description identifies the outcome population as randomized participants who received at least 1 dose of active study therapy. That definition should be distinguished from an intention-to-treat population that would include all randomized participants regardless of treatment received. The record's stated population is the basis for the posted endpoint description; further analysis-population details are not reported.
11. Confidence Intervals and Precision
The primary endpoint is reported with 80% confidence intervals. These intervals communicate uncertainty around each group percentage, and several are broad. The genotype 1b treatment-naive group receiving daclatasvir plus simeprevir without ribavirin had a reported percentage of 84.9 with an interval from 78.6 to 91.2. The genotype 1b null-responder group receiving that regimen had a percentage of 69.6 with an interval from 57.3 to 81.9. For genotype 1b groups receiving ribavirin, the intervals were 66.7 to 82.3 for treatment-naive participants and 88.8 to 100.0 for null responders.
The genotype 1a treatment-naive group receiving ribavirin had an interval from 49.2 to 84.1 around its reported percentage of 66.7. The genotype 1a null-responder group had a reported percentage of 0.0, but interval limits are not posted. That missing interval is not reported in the registry record. The zero estimate should therefore not be read as a precise estimate of the underlying response percentage.
As a general statistical explanation, an interval reflects uncertainty in an estimate under a particular calculation method; it is not a range containing a known fixed share of individual participant outcomes. The posted confidence level is 80%, so these intervals should be interpreted at that level. The recalculated risk-difference intervals for the posted comparisons include zero, indicating that the estimates do not precisely distinguish a difference from no difference under those calculations. The combination of small groups and broad intervals makes close ranking of the percentages unreliable.
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.
| Effect to detect | Participants per arm, 80% power | Participants per arm, 90% power |
|---|---|---|
| 100% of the observed effect | 117 | 155 |
| 75% of the observed effect | 195 | 260 |
| 50% of the observed effect | 409 | 547 |
The sample-size figures are planning illustrations based on the observed group effects, not the original design assumptions for the trial. For these binary outcomes, the listed figures are participants per arm. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers detecting the stated fraction of the observed effect. The trial's own original sample-size justification and design assumptions are not reported in the registry record.
The 80% power column gives the illustrative participants per arm for a design with an 80% chance of detecting the specified effect if the planning assumptions hold. The 90% power column gives the corresponding per-arm figure for a design with a 90% chance. These are design-planning quantities, not guarantees that a future study will detect an effect. For example, planning for 75% of the observed effect in the primary comparison between the genotype 1b treatment-naive reference group and the genotype 1b null-responder group without ribavirin gives 195 participants per arm for 80% power and 260 for 90% power.
Smaller effects are harder to distinguish from random variation, so the illustrations require more participants per arm when the assumed effect is reduced. The rows using 50% of the observed effect therefore call for more participants than the rows using the full observed effect. These sample-size figures are planning illustrations and are not observed power; observed results do not determine the probability that a completed trial's finding is true.
The accompanying curve should be read in the same planning context: it relates assumed effect size to a projected sample requirement under the stated assumptions. It does not reconstruct the trial's actual design process or account for assumptions that the registry record does not report.
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 z1−α/2 = 1.960) and the desired power (z1−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
- Control proportion p0 = 0.849; treatment proportion p1 = 0.696; average p̄ = 0.772.
- First term: z1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5930 = 1.1623.
- Second term: z1−β × √[p0(1−p0) + p1(1−p1)] = 0.842 × 0.5830 = 0.4907.
- n = (1.1623 + 0.4907)2 / (-0.1534)2 = 116.1, rounded up to 117 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 <- 0.849056603773585 # control proportion
p1 <- 0.695652173913043 # 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(1628692)
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 = 117 (80% power), 155 (90% power)
75% of observed effect: n per arm = 195 (80% power), 260 (90% power)
50% of observed effect: n per arm = 409 (80% power), 547 (90% power)
power.prop.test: 116.1
Simulated power at n = 117 per arm: 0.806 (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 registry lists a primary endpoint and multiple secondary outcomes, and the posted results include several treatment-group comparisons. The registry record does not report how the original analysis plan handled multiplicity, whether a particular endpoint hierarchy was specified, or whether any adjustment was planned for testing multiple outcomes or contrasts. It also reports no formal analyses. The recalculated p-values are unadjusted and should not be interpreted as though they account for the number of comparisons examined.
As a general statistical explanation, when multiple hypotheses are tested, the chance of obtaining at least one apparently unusual result by chance can rise. A prespecified hierarchy or multiplicity adjustment can help control how confirmatory claims are made. Without a reported procedure, emphasis should remain on estimates, intervals, the primary endpoint definition, and the limitations of unadjusted comparisons, rather than selecting individual results as decisive.
Missing-data handling is also not reported in the registry record. The primary outcome population is described as randomized participants who received at least 1 dose of active study therapy, but the record does not state how participants without a post-treatment Week 12 measurement were classified or whether any imputation method was used. The number and reasons for missing primary endpoint measurements are not reported in the registry record.
The registry record does not report whether interim analyses occurred, the trial's original statistical analysis plan, or the details of any adjustment for baseline characteristics. It also does not provide enough detail to establish how the randomized allocation was implemented across the posted genotype and prior-response groups. These omissions limit assessment of the intended confirmatory framework. They do not justify assuming that a particular method was or was not used; the relevant details are simply not reported in the registry record.
15. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) | 7 | 76 | 9.2% |
| Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | 3 | 71 | 4.2% |
| Genotype1a: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | 1 | 21 | 4.8% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) | 49 of 76 |
| Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | 63 of 71 |
| Genotype1a: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | 21 of 21 |
Most frequent serious adverse event terms
| Event term | Organ system | Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) | Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | Genotype1a: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) |
|---|---|---|---|---|
| Pneumonia | Infections and infestations | 1 of 76 | 1 of 71 | 0 of 21 |
| Intracranial haematoma | Nervous system disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Thrombophlebitis superficial | Vascular disorders | 0 of 76 | 1 of 71 | 0 of 21 |
| Liver disorder | Hepatobiliary disorders | 0 of 76 | 1 of 71 | 0 of 21 |
| Hypoaesthesia | Nervous system disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Ischaemic stroke | Nervous system disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Neurotoxicity | Nervous system disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Depression | Psychiatric disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Constipation | Gastrointestinal disorders | 1 of 76 | 0 of 71 | 0 of 21 |
| Hepatic cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 76 | 0 of 71 | 1 of 21 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) | Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) | Genotype1a: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) |
|---|---|---|---|---|
| Asthenia | General disorders | 15 of 76 | 16 of 71 | 5 of 21 |
| Headache | Nervous system disorders | 16 of 76 | 10 of 71 | 6 of 21 |
| Nausea | Gastrointestinal disorders | 14 of 76 | 11 of 71 | 4 of 21 |
| Pruritus | Skin and subcutaneous tissue disorders | 5 of 76 | 15 of 71 | 5 of 21 |
| Fatigue | General disorders | 6 of 76 | 11 of 71 | 7 of 21 |
| Nasopharyngitis | Infections and infestations | 10 of 76 | 9 of 71 | 2 of 21 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 4 of 76 | 11 of 71 | 2 of 21 |
| Hyperbilirubinaemia | Hepatobiliary disorders | 1 of 76 | 12 of 71 | 3 of 21 |
| Rash | Skin and subcutaneous tissue disorders | 3 of 76 | 9 of 71 | 3 of 21 |
| Constipation | Gastrointestinal disorders | 6 of 76 | 5 of 71 | 4 of 21 |
Serious events with the highest arm-level rate: hepatic cancer (4.8%), thrombophlebitis superficial (1.4%), liver disorder (1.4%), pneumonia (1.4%), intracranial haematoma (1.3%).
The posted safety groups combine treatment-naive participants and null responders within each regimen and genotype grouping. In the genotype 1b group receiving daclatasvir plus simeprevir without ribavirin, 7 serious adverse events were reported among 76 participants at risk. In the genotype 1b group receiving the combination with ribavirin, 3 serious adverse events were reported among 71 at risk. In the genotype 1a group receiving the combination with ribavirin, 1 serious adverse event was reported among 21 at risk.
The record also reports other adverse events in these groups: 49 among 76, 63 among 71, and 21 among 21, respectively. These are event counts as posted, not necessarily counts of participants with at least one event. The record lists serious-event terms including hepatic cancer at 4.8%, thrombophlebitis superficial at 1.4%, liver disorder at 1.4%, pneumonia at 1.4%, intracranial haematoma at 1.3%, and hypoaesthesia at 1.3%. The record does not specify in this summary how those term percentages relate to each group.
Deaths are not reported in the registry record. The pooled groupings, different group sizes, and lack of detailed attribution limit comparisons. These figures describe reported events; they do not by themselves establish that a regimen caused an event or support a direct safety ranking.
16. What the Result Does, and Does Not, Mean
The posted results describe SVR12 percentages in groups of participants defined by hepatitis C genotype, prior treatment history, and study regimen. The percentages answer a specific question: what share of each stated analysis group met the registry's laboratory-based response definition at post-treatment Week 12? The confidence intervals show that the estimates are uncertain, particularly where group sizes are small. The posted comparisons are unadjusted recalculations, and their intervals include no difference.
These results do not establish that one regimen is superior to another, that the groups are equivalent, or that ribavirin alone accounts for observed differences. The groups differ in characteristics beyond the presence or absence of ribavirin, including genotype and prior treatment response. The registry record does not report an adjusted comparison designed to separate those factors. The reported percentages should be interpreted as results for the specific posted groups, not as universal estimates for all people with hepatitis C.
The outcome is a virologic laboratory measure, not a complete account of health, symptoms, long-term outcomes, or quality of life. Such outcomes are not reported in the primary endpoint description. The posted safety data list adverse-event counts, but the summaries do not establish causality or provide a complete basis for comparing safety across groups.
As a general statistical point, lack of a clearly resolved difference is not proof that two treatments have the same effect. Conversely, a numerical difference between observed percentages does not by itself establish a true or clinically important difference. Those conclusions depend on design, analysis, precision, and the question being asked. The registry record does not report several details needed for a full assessment, including the original statistical plan and missing-data methods. The careful interpretation is therefore descriptive: the record reports group-specific response and safety observations, with uncertainty and important limits on causal comparison.
17. Why This Trial Matters Statistically
This study illustrates why a clinical trial's group structure matters as much as its headline outcome. The posted SVR12 percentages are organized by genotype and prior treatment response as well as by regimen. A direct comparison between groups can therefore combine differences in treatment with differences in the populations being compared. Recognizing that structure prevents a descriptive contrast from being mistaken for an isolated treatment effect.
The record also demonstrates the value of reading estimates together with their intervals. Percentages can appear quite different while remaining imprecise, particularly in small groups. The 80% confidence intervals and unadjusted risk-difference intervals make that uncertainty visible. For the posted risk-difference comparisons, the intervals include no difference, so the numerical ordering of the point estimates should not be treated as a firm ranking.
Finally, the trial highlights the distinction between a published endpoint list and a complete statistical analysis record. Some outcomes have numerical results while others listed in the record do not, and the original statistical plan, missing-data methods, and multiplicity approach are not reported. Those omissions affect how much confirmatory weight can be placed on the findings. For biostatisticians and clinical researchers, the key statistical task is to separate what the data describe from what the design and reported analysis can support.
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.
Several features of this specific record constrain interpretation. The treatment groups span genotype 1a and 1b and treatment-naive and null-responder populations. The posted unadjusted contrasts use a genotype 1b treatment-naive group without ribavirin as the reference, so the other contrasts are not matched on all these characteristics. The registry record does not report an adjusted analysis that separates regimen differences from genotype or prior-response differences.
The study was open-label, with no masking. The registry does not report details of outcome assessment procedures beyond the central laboratory assay description for SVR12. The group sizes vary, and some are small; the genotype 1a null-responder group has a reported SVR12 of 0.0 with no confidence interval limits posted. The absence of interval limits is not reported in the registry record, so the precision of that estimate cannot be assessed from the displayed result alone.
The registry record does not report the original sample-size justification, the planned analysis method, handling of missing outcomes, multiplicity procedures, interim analyses, or detailed allocation methods. Numerical results are not reported in the registry record for every listed outcome. The safety summaries pool treatment-history categories and do not, in this summary, give enough detail to attribute the listed serious-event terms to specific groups. Deaths are not reported in the registry record.
These limitations do not invalidate the descriptive results, but they restrict the strength and scope of conclusions that can be drawn from them.
19. Related Tutorials
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus — NCT01628692.
- Registry record last updated 2017-02-23; status last verified 2017-01.
- Results first posted 2015-11-30.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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22. Record Summary
The registry record describes a completed, randomized, open-label, parallel Phase 2 study of daclatasvir and simeprevir, with or without ribavirin, in treatment-naive participants and null responders with genotype 1 chronic hepatitis C. Enrollment was 230. The primary endpoint was the percentage with SVR12, defined using hepatitis C virus RNA at post-treatment Week 12.
Posted primary results vary across groups defined by genotype, treatment history, and regimen. The reported intervals and unadjusted recalculations do not establish a clear difference between the posted comparison groups. Several early virologic outcomes and grouped safety summaries are also reported, but numerical results for some listed outcomes are not reported in the registry record. Details of the original statistical plan, missing-data handling, and multiplicity procedures are not reported.