A Study to Evaluate the Safety and Effect of Co-administration of ABT-450 With Ritonavir (ABT-450/r) and ABT-267 in Adults With Chronic Hepatitis C Virus Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Effect of Co-administration of ABT-450 With Ritonavir (ABT-450/r) and ABT-267 in Adults With Chronic Hepatitis C Virus Infection (NCT01685203), a randomized phase 2 study. The primary outcome is Percentage of Participants in Each Treatment Group With Sustained Virologic Response 12 Weeks Post-treatment.

2. Clinical Question

3. Trial Design

NCT01685203 was a randomized, open-label, parallel-group phase 2 study of adults with chronic hepatitis C. The registry lists enrollment of 316 and status as completed. The recorded start was 2012-08, and primary completion was 2014-06. No masking was used. The purpose was to evaluate the safety and efficacy of co-administering ABT-450 with ritonavir and ABT-267, with ribavirin included in some groups.

The groups were not interchangeable populations. Group 1 comprised noncirrhotic, treatment-naïve adults with HCV genotype 4 who received ABT-450/r and ABT-267 for 12 weeks. Group 2 had noncirrhotic, treatment-naïve genotype 1b infection and received the same named combination for 12 weeks. Group 3 had noncirrhotic genotype 1b infection and a null response to prior pegylated interferon/ribavirin treatment; its described course was also 12 weeks. Group 4 matched the genotype 4 treatment-naïve description of Group 1 but added ribavirin.

Group 6 comprised noncirrhotic genotype 4 participants with prior pegylated-interferon/ribavirin treatment experience and received ribavirin with the combination. Groups 7 and 8 had genotype 1b infection with compensated cirrhosis and received the combination for 24 weeks; Group 7 was treatment-naïve and Group 8 treatment-experienced. Group 5 is described as noncirrhotic, treatment-experienced genotype 4 receiving the combination for 12 weeks, but its outcome results are not reported in the registry record.

Randomization is recorded, but the allocation procedure, details of assignment within or across these distinct groups, and the trial’s original sample-size justification are not reported in the registry record. The available descriptions therefore support careful reading of each group’s response and of the specific registry analyses, rather than treating every pairwise contrast as if it arose from a single common population.

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: The study originally planned to enroll Group 5 (GT4 treatment-experienced, 2-DAA regimen for 12 weeks), but based on a protocol-specified interim review of results from the treatment-naïve GT4 Groups 1 and 4 that indicated higher SVR rates among participants receiving the 2-DAA regimen with RBV, Group 5 was not opened to enrollment.

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: All randomized participants who received at least 1 dose of study drug.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: All participants who received at least 1 dose of study drug.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants in Each Treatment Group With Sustained Virologic Response 12 Weeks Post-treatment, measured over 12 weeks after the last actual dose of study drug.

The primary endpoint is the percentage of participants with sustained virologic response 12 weeks after the last actual dose of study drug. A participant met the registry definition when plasma hepatitis C virus RNA was below the lower limit of quantitation at that follow-up. The endpoint population is all randomized participants who received at least 1 dose of study drug.

This endpoint captures whether the measured viral RNA response persists after the treatment course rather than only while study drug is being taken. In general, a defined laboratory threshold makes an endpoint more operational: participants are classified according to whether their measurement falls below that threshold at a specified follow-up. The threshold and timing are part of the endpoint definition, not a statement about how to interpret an individual’s health.

The registry reports a percentage for each posted treatment group and a 95% confidence interval around each percentage. Those estimates describe the observed response proportions and the uncertainty associated with them. The groups differ in genotype, prior treatment, cirrhosis status, ribavirin use, and treatment duration, so the endpoint values should be understood in the context of each group’s eligibility and regimen. They do not, by themselves, establish that one component of a regimen caused a difference between groups.

The registry record does not report a broader primary analysis plan, such as how all groups were intended to be compared together. It does identify selected pairwise analyses separately. The endpoint is therefore useful for describing post-treatment response in the enrolled groups, while the design and analysis details limit what can be concluded from cross-group differences.

7. Results Posted in the Registry

• Group 2: 95.2% (40/42) versus 90.9% (40/44) on control; risk difference 4.3 percentage points (95% CI -6.3 to 15.0), risk ratio 1.05 (0.93–1.18); unadjusted two-proportion z-test p = 0.431.
• Group 3: 90.0% (36/40) versus 90.9% (40/44) on control; risk difference -0.9 percentage points (95% CI -13.5 to 11.7), risk ratio 0.99 (0.86–1.14); unadjusted two-proportion z-test p = 0.887.
• Group 4: 100.0% (42/42) versus 90.9% (40/44) on control; risk difference 9.1 percentage points (95% CI 0.6 to 17.6), risk ratio 1.10 (1.00–1.21); unadjusted two-proportion z-test p = 0.045.
• Group 6: 100.0% (49/49) versus 90.9% (40/44) on control; risk difference 9.1 percentage points (95% CI 0.6 to 17.6), risk ratio 1.10 (1.00–1.21); unadjusted two-proportion z-test p = 0.031.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants in Each Treatment Group With Sustained Virologic Response 24 Weeks Post-treatment

• 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:
  • Group 2: 92.9% (39/42) versus 86.4% (38/44) on control; risk difference 6.5 percentage points (95% CI -6.3 to 19.3), risk ratio 1.08 (0.93–1.24); unadjusted two-proportion z-test p = 0.325.
  • Group 3: 90.0% (36/40) versus 86.4% (38/44) on control; risk difference 3.6 percentage points (95% CI -10.1 to 17.4), risk ratio 1.04 (0.89–1.22); unadjusted two-proportion z-test p = 0.607.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 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 Group 3 and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants in Each Treatment Group With On-treatment Virologic Failure.

• 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:
  • Group 2: 0.0% (0/42) versus 2.3% (1/44) on control; risk difference -2.3 percentage points (95% CI -6.7 to 2.1); unadjusted two-proportion z-test p = 0.326.
  • Group 3: 2.5% (1/40) versus 2.3% (1/44) on control; risk difference 0.2 percentage points (95% CI -6.3 to 6.8), risk ratio 1.10 (0.07–17.01); unadjusted two-proportion z-test p = 0.946.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 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 Group 3 and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants in Each Treatment Group With Post-treatment Virologic Relapse.

• 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:
  • Group 2: 0.0% (0/40) versus 4.8% (2/42) on control; risk difference -4.8 percentage points (95% CI -11.2 to 1.7); unadjusted two-proportion z-test p = 0.162.
  • Group 3: 7.7% (3/39) versus 4.8% (2/42) on control; risk difference 2.9 percentage points (95% CI -7.6 to 13.5), risk ratio 1.62 (0.28–9.16); unadjusted two-proportion z-test p = 0.584.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 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 Group 3 and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the primary assessment in related ways: sustained virologic response 24 weeks after treatment, on-treatment virologic failure, post-treatment virologic relapse, and treatment-emergent adverse events are among the registered outcomes. The posted data include results for sustained response at 24 weeks, virologic failure, and relapse. Together, these outcomes provide context about response after treatment and events during or after the course, rather than replacing the primary 12-week post-treatment response measure.

Across the posted arms, the 24-week sustained-response percentages follow a broadly similar pattern to the primary results. The recorded percentages for on-treatment virologic failure and post-treatment relapse are mostly zero or low, with uncertainty intervals that can still be wide in these small groups. These broad patterns are consistent with describing the posted response results as generally high and the recorded virologic events as uncommon; they do not establish a comparative advantage for one group. The group differences in eligibility and regimen still apply to these secondary outcomes.

Secondary results typically carry less weight for confirmatory claims when there are multiple outcomes, time points, groups, or pairwise comparisons. Each additional analysis creates more opportunities for a result to appear unusual by chance. In general, multiplicity procedures can control that risk, but the registry does not report a multiplicity plan or enough information to determine how these results were prioritized. The registry also does not provide sponsor analyses for the posted secondary comparisons described in the record.

Secondary endpoints can be valuable for understanding whether the overall pattern is coherent and for identifying questions that warrant further study. Their interpretation should remain exploratory unless a prespecified analysis plan and suitable multiplicity handling are available. The broad agreement between post-treatment response measures does not remove uncertainty in the individual group estimates, nor does it resolve the limited comparability among groups.

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

• Percentage of Participants in Each Treatment Group With Sustained Virologic Response 24 Weeks Post-treatment
• Percentage of Participants in Each Treatment Group With On-treatment Virologic Failure.
• Percentage of Participants in Each Treatment Group With Post-treatment Virologic Relapse.
• Percentage of Participants in Each Treatment Group With Treatment-emergent Adverse Events

9. Statistical Interpretation

10. Statistical Methods Explained

The registry presents the primary outcome as a binary percentage: each participant either met the sustained-response definition at the specified follow-up or did not. The percentage is the group-level summary of that classification. In general, binary outcomes can be summarized as proportions, and a comparison between groups can be expressed as a risk difference. A risk difference describes the subtraction of one group’s event proportion from another’s; positive or negative direction depends on which group is designated as the reference. The recalculated contrasts use Group 1 as that reference.

What does a confidence interval express?

A confidence interval describes uncertainty in an estimated quantity under the method used to calculate it. In general, a wider interval indicates less precision, while a narrower interval indicates more precision. For a group percentage, the interval concerns the underlying response proportion compatible with the observed data and method. For a risk difference, an interval that includes zero is compatible with no difference under that calculation, as well as with differences in either direction. This interpretation does not prove equivalence or absence of an effect.

The reported primary outcome gives a 95% confidence interval for each group’s percentage. The recalculated comparisons give intervals for unadjusted risk differences. These are not the same estimand: one describes a group’s response proportion and the other describes a difference between two proportions. The registry also reports relative risks for several contrasts and odds ratios for some, but these measures answer different questions from an absolute difference. The core interpretation focuses on proportions and risk differences because they are directly readable in percentage-point terms when expressed as percentages.

How are the registry analyses different from recalculations?

The sponsor’s reported analyses identify logistic regression for Group 2 versus Group 3 and a stratum-adjusted Mantel-Haenszel method for Group 1 versus Group 4. The registry gives p-values of 0.381 and 0.086, respectively, for those analyses, but does not provide an effect estimate or confidence interval for either. The recalculated contrasts are simple, unadjusted comparisons from the posted outcome counts and group sizes. They do not reproduce the sponsor’s regression or stratum adjustment, and they do not account for covariates or stratification. General statistical practice treats adjusted and unadjusted analyses as distinct analyses, not as interchangeable versions of the same calculation.

For Group 1 versus Group 4, the recalculated risk difference is 0.091, with a 95% confidence interval from 0.006 to 0.176 and an unadjusted p-value of 0.045. The sponsor’s stratum-adjusted analysis reports p = 0.086. The discrepancy means those results should not be combined or selectively treated as if they were one analysis. The sponsor’s own analysis takes precedence for that comparison. The registry’s Group 2 versus Group 3 result is not the same comparison as either group’s separate recalculated contrast against Group 1.

Why does group structure matter?

In general, a randomized comparison is most interpretable when the compared groups were assigned under a design that makes them comparable for the question being asked. Here, the group descriptions identify different genotypes, treatment histories, cirrhosis statuses, regimens, or treatment durations. The record says the study was randomized, but does not report enough allocation detail to establish that every pairwise comparison in the recalculated summaries was a planned randomized contrast. Therefore, use those calculations as descriptive comparisons of posted group results rather than as definitive estimates of an isolated treatment effect.

Open-label status means masking was absent. In general, lack of masking can influence expectations, reporting, or other aspects of trial conduct. The primary endpoint is based on plasma HCV RNA, a laboratory measure, which reduces reliance on subjective symptom reporting for that endpoint; however, masking details alone do not resolve other design or analysis uncertainties.

What is not known from the record?

The statistical analysis plan, original sample-size justification, planned handling of multiplicity, interim analyses, and missing-data procedures are not reported in the registry record. The endpoint population is explicitly described as randomized participants who received at least 1 dose; this is not enough to infer that the primary analysis was a full intention-to-treat analysis. The number of participants included in each endpoint estimate is reported, but the record does not explain all reasons for differences between randomized, treated, and analyzed populations. These limits matter when assessing how well the posted results represent the original trial plan.

11. Confidence Intervals and Precision

The group-specific 95% confidence intervals show the uncertainty around each primary response percentage. Group 1’s estimate of 90.9% has an interval from 78.3% to 97.5%; Group 2’s estimate of 95.2% has an interval from 83.8% to 99.4%; and Group 3’s estimate of 90.0% has an interval from 76.3% to 97.2%. Those intervals allow a broad range of underlying response percentages. Groups with an observed value of 100.0% also have uncertainty: the lower limits are 91.6% for Group 4 and 92.7% for Group 6.

For the unadjusted primary contrasts with Group 1, the intervals for Groups 2, 3, 7, and 8 include zero. The intervals for Groups 4 and 6 run from 0.006 to 0.176. These intervals quantify uncertainty under the recalculation method; they do not account for the registry’s distinct sponsor analysis or resolve possible multiplicity. In general, a confidence interval is not a probability statement that the true value lies within the particular calculated interval. It is a measure of the method’s uncertainty over repeated use under its assumptions.

The group sizes are modest, ranging among posted primary estimates from 40.0 to 52.0 participants. With small groups, each participant can have a substantial influence on a percentage, and extreme observed proportions such as 100.0% can still have confidence intervals with meaningful width. The precision displayed should therefore temper conclusions based only on the ordering of point estimates. Overlap between group-specific intervals is not itself a formal test of a difference; the risk-difference interval is more directly aligned with uncertainty in the group contrast.

The registry does not report confidence intervals for the sponsor’s two listed analyses. It gives their p-values but no corresponding effect estimates or interval limits. Consequently, the precision of those sponsor analyses cannot be judged from the reported p-values alone. The record also does not report a prespecified clinically important difference, so statistical precision cannot be translated into a judgment about clinical importance.

12. Planning a Similar Trial: Sample Size

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

The sample-size illustrations use the observed effect in a pairwise comparison as a starting point and show planning values for detecting the full observed effect, 75% of the observed effect, or 50% of the observed effect. For binary endpoints, the figures are participants per arm, not totals across both arms. The planning assumptions listed are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column means the illustrative number of participants per arm under which the assumed calculation would have an 80% chance of detecting the specified effect if that effect were the true one and the assumptions held. The 90% power column uses a higher target probability of detecting that effect, so it generally calls for more participants per arm. These values are planning illustrations based on the observed effect, not a reconstruction of the study’s original design.

Smaller effects are harder to distinguish from random variation, so the illustrations generally require more participants when the target is a smaller fraction of the observed effect. The displayed values can become very large when the observed difference is small; this reflects the consequences of planning to detect a subtle contrast under the stated assumptions, not evidence that a future study would necessarily need exactly that enrollment. Different group populations and the unadjusted nature of the observed contrast also limit how directly these illustrations transfer to a new design.

These numbers are not observed power. Observed power is not an informative substitute for reading the effect estimate and its confidence interval after a study is completed. The sample-size values instead illustrate possible future planning under stated assumptions. They should not be read as the study’s actual target, or as evidence that the trial was or was not adequately sized, because the original design justification is not reported in the registry record.

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 = 0.909; treatment proportion p₁ = 0.952; average p̄ = 0.931.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3591 = 0.7038.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3578 = 0.3011.
4. n = (0.7038 + 0.3011)² / (0.0433)² = 538.8, rounded up to 539 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 <- 0.909090909090909                          # control proportion
p1 <- 0.952380952380952                          # 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(1685203)
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 = 539 (80% power), 721 (90% power)
 75% of observed effect: n per arm = 1,028 (80% power), 1,376 (90% power)
 50% of observed effect: n per arm = 2,468 (80% power), 3,303 (90% power)
power.prop.test: 538.8 
Simulated power at n = 539 per arm: 0.808 (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 lists two sponsor analyses. Group 2 versus Group 3 was analyzed using logistic regression, with p = 0.381. Group 1 versus Group 4 was analyzed using a stratum-adjusted Mantel-Haenszel method, with p = 0.086. The record does not give effect estimates or confidence intervals for these sponsor analyses, so the magnitude and precision of their adjusted contrasts cannot be read from those p-values alone.

The recalculated figures are simple unadjusted comparisons based on the posted group counts and percentages. For Group 1 versus Group 4, the recalculated risk difference is 0.091, its 95% confidence interval runs from 0.006 to 0.176, and the unadjusted p-value is 0.045. This differs from the sponsor’s stratum-adjusted p-value of 0.086. Because the registry record flags a discrepancy, the sponsor’s own analysis takes precedence for this comparison; the unadjusted recalculation is supplementary and should not override it.

The sponsor’s Group 2 versus Group 3 analysis is not the same contrast as the separately recalculated comparisons of each group against Group 1. A p-value from one contrast cannot be substituted for another. The registry does not list a sponsor analysis corresponding to the recalculated Group 6 versus Group 1 comparison. The analysis methods and estimands must therefore remain distinct when interpreting the reported results.

15. Multiplicity, Missing Data and Analysis Populations

The record lists a primary endpoint, several secondary endpoints, multiple treatment groups, and selected pairwise analyses. When many outcomes or comparisons are examined, the chance of obtaining at least one apparently notable result by chance can increase. In general, multiplicity procedures address that issue by defining how statistical evidence is evaluated across a family of tests. The registry record does not report whether any multiplicity adjustment was planned or applied, how analysis families were defined, or which comparisons were intended to be confirmatory.

This omission is important when reading the recalculated unadjusted p-values. Those values correspond to individual comparisons and should not be treated as if they were adjusted for the full set of groups and outcomes. The sponsor’s reported Group 1 versus Group 4 analysis is stratum-adjusted, but the registry does not say that this adjustment addresses multiplicity. Statistical adjustment for strata and adjustment for multiple testing are different issues.

The endpoint population is described as all randomized participants who received at least 1 dose of study drug. That definition excludes randomized participants who did not receive a dose, but the record does not explain how many such participants there were or how they were handled. The registry gives group denominators for the posted outcomes; it does not report the missing-data method, reasons for missing measurements, or sensitivity analyses. Those details are needed to assess whether incomplete follow-up could affect the response estimates.

The registry records randomization and no masking, but does not report the allocation sequence, concealment procedures, stratification factors for randomization, or interim analyses. The original sample-size justification and full statistical analysis plan are also not reported in the registry record. These absences do not show that a procedure was not used; they mean its use and its implications cannot be evaluated from the registry entry. The posted results can still be described, but stronger confirmatory interpretation would require the prespecified analysis details.

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: device extrusion (2.5%), chronic obstructive pulmonary disease (2.4%), atrial fibrillation (2.3%), contusion (2.3%), road traffic accident (2.3%).

The registry lists serious adverse events by group, including the number of participants at risk and the number affected. Group 1 had 2 serious adverse events among 44 participants at risk; Group 2 had 1 among 42; and Group 3 had 1 among 40. Group 4 had 0 among 42, and Group 6 had 0 among 49. Group 7 had 3 among 47, and Group 8 had 2 among 52. These are counts, not evidence that a particular drug caused an event.

Zero recorded serious events in a group does not establish that the underlying risk is zero, particularly with these group sizes. Conversely, the counts alone do not establish a comparative safety difference. The groups differ in participant characteristics and regimen, and the registry record does not provide a causal safety analysis. Death counts are not reported in the registry record.

The record also lists serious-event terms and percentages, including device extrusion at 2.5%, chronic obstructive pulmonary disease at 2.4%, atrial fibrillation at 2.3%, contusion at 2.3%, road traffic accident at 2.3%, and oesophageal varices haemorrhage at 2.1%. These terms describe reported events; the list does not establish that study treatment caused them. The registry’s adverse-event results should be read as descriptive safety reporting for the posted groups.

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

The primary endpoint describes the proportion of treated, randomized participants in each posted group whose plasma HCV RNA was below the lower limit of quantitation 12 weeks after the last actual dose. The observed percentages are high across the groups with available results, from 90.0% to 100.0%. The confidence intervals show that the underlying response proportions remain uncertain, especially with the modest group sizes. The observed values are therefore estimates, not exact truths about the groups or guarantees for individuals.

The comparisons require particular care. Group 1 is used as the reference in the unadjusted recalculations, but it is not an untreated control. The groups differ in genotype, prior treatment experience, cirrhosis status, ribavirin use, and treatment duration. A higher observed percentage in one group cannot be attributed to a single regimen component from these data alone. The registry’s randomized designation does not resolve this limitation unless the specific comparison and assignment structure are clear.

The sponsor’s reported analysis for Group 1 versus Group 4 differs from the unadjusted recalculation. The registry record flags a discrepancy, so the sponsor’s own analysis takes precedence for that comparison. The two reported sponsor p-values do not provide effect sizes or confidence intervals, and the record does not report a complete statistical analysis plan or multiplicity strategy. This limits the strength of claims that can be made from isolated p-values.

The results do not establish how the regimens compare in populations not described in the trial, nor do they establish the effect of any one drug apart from the combinations and group differences. They do not establish long-term outcomes beyond the registered follow-up measures, or resolve missing-data and analysis-population questions that are not detailed in the registry. They also do not establish that an observed event was caused by treatment. The appropriate reading is a set of descriptive clinical-trial results with meaningful uncertainty and limitations in comparative interpretation.

18. Why This Trial Matters Statistically

This trial illustrates why a high observed response percentage is only part of a statistical interpretation. Estimates need to be read with their confidence intervals, group sizes, endpoint definition, and comparison structure. Even when the point estimates appear close to the upper end of the percentage scale, the uncertainty intervals show that the underlying response proportions are not known exactly. A group with 100.0% observed response still has a lower confidence limit below that value.

It also demonstrates the distinction between a posted descriptive recalculation and a sponsor’s analysis. A simple unadjusted risk difference is transparent and useful for describing the observed contrast, but it may not match an analysis that adjusts for strata or uses a regression model. When the registry flags a discrepancy, the sponsor’s analysis takes precedence for the comparison it addresses. Reporting both without explaining their different methods could lead readers to overemphasize whichever p-value seems more favorable.

The different populations and regimens are statistically central, not incidental. Genotype, prior treatment, cirrhosis status, ribavirin use, and treatment duration vary across groups. That means a collection of group percentages is not automatically a set of head-to-head estimates of treatment effects. Interpreting a contrast requires knowing which question was randomized, which analysis was planned, and how the groups were formed.

Finally, sample-size illustrations based on observed effects show how much planning estimates can depend on the assumed effect size. Smaller target effects require larger studies under the stated assumptions. But those illustrations cannot substitute for the original design rationale, which is not reported in the registry record. The study is therefore a useful example of the need to separate observed results, statistical uncertainty, analysis choices, and design information.

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 trial includes several clinically distinct groups rather than a single population with one uniform comparison. The group descriptions vary by HCV genotype, prior treatment experience, cirrhosis status, ribavirin use, and treatment duration. This limits direct interpretation of between-group differences and makes broad rankings of regimens inappropriate without further design and analysis detail. Group 1 serves as a reference in the recalculations but is not an untreated comparator.

Although randomization is recorded, the registry does not report how assignment operated across the distinct groups or whether every recalculated pair was a planned randomized comparison. The trial was open-label, with no masking. The primary outcome is laboratory-defined, but open-label conduct can still matter for other aspects of trial conduct and for subjective outcomes. The registry does not give details on allocation concealment or the full protocol.

Group 5 has a treatment description but no posted outcome results in the record. This leaves the trial’s described treatment groups incompletely represented in the available outcome summaries. The record also does not report the original sample-size justification, missing-data procedures, interim analyses, complete analysis plan, or multiplicity handling. These omissions limit assessment of whether the posted analyses correspond to prespecified aims and how robust the results are to missing information or multiple comparisons.

The sponsor reports only two analyses in the record, and their effect estimates and confidence intervals are absent. One of those analyses differs from the unadjusted recalculation. The additional calculated comparisons are simple unadjusted summaries and should not be mistaken for the sponsor’s full analysis. Finally, the registry’s adverse-event counts are descriptive; death counts are not reported in the registry record, and the event-term list does not establish causality.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Effect of Co-administration of ABT-450 With Ritonavir (ABT-450/r) and ABT-267 in Adults With Chronic Hepatitis C Virus Infection — NCT01685203.
• Registry record last updated 2021-07-30; status last verified 2021-07.
• Results first posted 2015-08-04.
• 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

NCT01685203 was a completed randomized, open-label, parallel-group phase 2 study in adults with chronic hepatitis C, with enrollment of 316. The trial assessed ABT-450/r with ABT-267, with ribavirin included in some groups. Group descriptions span different genotypes, treatment histories, cirrhosis statuses, and treatment durations.

The primary outcome was sustained virologic response 12 weeks after the last actual dose, defined by plasma HCV RNA below the lower limit of quantitation. Posted percentages ranged from 90.0% to 100.0% across groups with results, with confidence intervals reflecting uncertainty. Group 5 has no posted outcome result. The registry reports two sponsor analyses and the record flags a discrepancy with recalculated results for a comparison; the sponsor’s own analysis takes precedence. Important details, including the original sample-size justification, multiplicity plan, and missing-data procedures, are not reported in the registry record.