Efficacy and Safety of Grazoprevir (+) Uprifosbuvir (+) Ruzasvir (MK-3682B) (MK-5172 + MK-3682 + MK-8408) Fixed Dose Combination in Chronic HCV Participants Failing Prior Antiviral Treatment (MK-3682-021): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Grazoprevir (+) Uprifosbuvir (+) Ruzasvir (MK-3682B) (MK-5172 + MK-3682 + MK-8408) Fixed Dose Combination in Chronic HCV Participants Failing Prior Antiviral Treatment (MK-3682-021) (NCT02613403), a randomized phase 2 study. The primary outcome is Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After The End of Study Therapy (SVR12).

2. Clinical Question

3. Trial Design

This was a phase II, randomized, open-label, parallel-group, multicenter clinical trial of MK-3682B, with or without ribavirin, in participants with chronic hepatitis C who had previously failed antiviral treatment. The registry records enrollment of 94 and lists the study status as terminated. The study had two parts, but the posted primary analysis concerns Part A only: Part B was terminated before participant enrollment and was not included in the analysis.

Part A separated participants according to the direct-acting antiviral regimen they had previously failed. Arms 1 and 2 enrolled participants with genotype 1 infection and prior sofosbuvir/ledipasvir failure. Arms 3 and 4 enrolled participants with genotype 1 infection and prior grazoprevir/elbasvir failure. Within each history, one arm received MK-3682B with ribavirin and another received MK-3682B without ribavirin. The ribavirin arms received 16 weeks of treatment; the arms without ribavirin received 24 weeks. Each arm included cirrhotic or non-cirrhotic participants.

Part B was planned to include participants with genotype 1 through genotype 6 infection after failure of an all-oral direct-acting antiviral regimen, or participants with genotype 3 infection after failure of sofosbuvir/peginterferon/ribavirin. Its planned regimen was MK-3682B for 16 weeks, but no Part B participants were enrolled. Consequently, the reported SVR12 estimates do not represent that broader planned population.

The open-label design means treatment assignment was not masked. The registry record does not report the randomization procedure, allocation concealment, or whether any outcome assessment was blinded. It also does not report the reason the trial was terminated or the rationale for the different treatment durations. Those details are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants in Part A receiving ≥1 dose of study treatment. Part B was terminated prior to participant enrollment and was not included for analysis.

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: Includes only randomized participants in Study Part A receiving ≥1 dose of study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After The End of Study Therapy (SVR12), measured over 12 weeks following final dose of study treatment ([MK-3682B + RBV Groups]: Study Week 28; [MK-3682B Groups]: Study Week 36).

The primary endpoint was the percentage of participants achieving sustained virologic response 12 weeks after the final dose of study therapy, abbreviated SVR12. A participant met the endpoint if plasma HCV RNA was below the lower limit of quantification 12 weeks after treatment ended. The registry specifies the Roche COBAS AmpliPrep/COBAS Taqman HCV Test, v2.0 assay and an LLOQ of 15 IU/mL. Assessment occurred at study week 28 for the MK-3682B plus ribavirin groups and at study week 36 for the MK-3682B groups, reflecting the different treatment durations.

SVR12 is a virologic endpoint: it describes whether virus was quantifiable in the participant’s plasma at a specified follow-up point. Reporting a percentage allows readers to see the proportion meeting that defined outcome in each arm, while the confidence interval conveys uncertainty around the estimate. The endpoint is used to assess a treatment’s virologic response after therapy has ended, rather than only measuring a change during treatment. It does not, on its own, describe every aspect of health, longer-term outcomes, or safety.

The primary analysis population was all randomized Part A participants who received at least one dose of study treatment. Part B was excluded because it was terminated before enrollment. The registry record does not state how missing SVR12 measurements were handled, or whether participants without an assessable result were counted as not achieving SVR12. Those analysis details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is reported as a percentage with a 95% confidence interval for each Part A arm. This presents both a point estimate and a measure of statistical uncertainty. The point estimate is the observed percentage meeting the endpoint in that arm. The interval gives a range of values compatible with the data under the method used to calculate it. It is not a guarantee that the true response lies within that particular interval, and it does not describe variation among individual participants.

The registry identifies the interval as a 95% confidence interval but does not state the interval calculation method. The registry record does not report whether the primary outcome analysis used a particular binomial interval, continuity adjustment, or other procedure. Those details should not be inferred from the displayed bounds. The intervals should be interpreted as posted rather than reverse-engineered into a specific analysis method.

Why do the 100.0% estimates still have uncertainty?

A percentage calculated from a finite group is an estimate, even when every analyzed participant in that group meets the endpoint. The underlying response rate is not known with certainty from the observed group alone. The lower bounds of the posted confidence intervals make that uncertainty visible: they are 90.3% and 66.4% in the two arms with 100.0% estimates, and 75.3% in the other arm with a 100.0% estimate. The interval widths differ across groups, in part because the arm sizes differ. The small prior grazoprevir/elbasvir groups have particularly broad intervals, so their point estimates should not be treated as highly precise.

General statistical explanation: when outcomes are expressed as proportions, uncertainty depends on the amount of information in the group and on the observed proportion. Near the boundary of 100%, ordinary approximations can behave differently from methods designed for proportions. The registry does not identify the calculation method, so no claim about the specific approach is warranted. The important reading point is that the reported bounds remain relevant even when the point estimate reaches 100.0%.

What does randomization contribute?

Random allocation is intended, in general, to reduce systematic differences between groups at assignment, supporting a fair comparison when outcomes are analyzed according to a defined plan. But randomization alone does not produce a comparative result. The record reports arm-specific percentages, not a treatment contrast with its own uncertainty. Nor does it describe how allocation was generated or concealed. The labels randomized and open-label describe the broad design: assignment was random, and treatment masking was absent. They do not supply unreported details about implementation or analysis.

In this trial, the arms are stratified by prior treatment history and also differ in ribavirin use and treatment duration. The results therefore need to be interpreted in their arm-specific context. General statistical principle: a contrast should be defined for groups that address the same clinical question, and the estimate should account for the trial’s design and analysis population. The registry does not report a pooled contrast, an adjusted estimate, or a direct comparison of ribavirin versus no ribavirin. The percentages should not be collapsed into a single comparison.

How should missing outcomes be considered?

The stated primary population consists of all randomized Part A participants who received at least one dose of treatment. This is a treatment-exposed randomized population, rather than every randomized participant regardless of treatment receipt. The record does not provide counts of participants with missing endpoint data, explain how missing measurements were treated, or state whether a sensitivity analysis assessed alternative assumptions. It is therefore not possible to determine from the registry record how missingness could affect the estimates. General statistical explanation: missing outcome data can change a proportion if the chance of missing measurement is related to the outcome; transparent reporting of denominators and handling rules helps readers evaluate that risk.

The record lists arm sizes and confidence intervals, but does not describe the statistical analysis plan, endpoint analysis method, adjustment variables, or interim analyses. These are not reported in the registry record. No unreported test, adjustment, or model should be assumed. There are also no secondary posted results listed, so the endpoint findings should be understood as the posted primary outcome information rather than as a complete account of every planned analysis.

Planning calculations, when presented, answer a different question from the observed trial results. General statistical explanation: a planning illustration uses assumptions about an effect and an analysis to show what sample size might be needed under those assumptions. It is not observed power and does not establish how likely the trial was to detect an effect after the results are known. The registry record’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as fractions of the observed effect. The registry does not report that these assumptions were the trial’s original design basis. The trial’s own sample-size justification is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome is identified as SVR12, and the registry lists four Part A arms. However, the registry record does not report a multiplicity strategy, such as how the type I error rate would be controlled across multiple planned comparisons or endpoints. It also does not report which pairwise contrasts, if any, were prespecified. Without that information, the posted arm-level confidence intervals should not be interpreted as a set of multiplicity-adjusted comparative tests.

The record lists nine outcome measures but posts no secondary results. It does not explain whether secondary outcomes were not analyzed, were analyzed but not posted, or were omitted for another reason. The statistical analysis plan, any hierarchy among endpoints, and any interim analyses are not reported in the registry record. The absence of those details prevents a full assessment of selective reporting or the role of the primary endpoint among planned analyses.

The primary population is described as all randomized participants in Part A who received at least one dose of study treatment. The record does not report how many otherwise eligible randomized participants did not receive a dose, nor does it explain how participants with missing SVR12 data were classified. No missing-data imputation method, sensitivity analysis, or alternative analysis population is described. These details are not reported in the registry record.

General statistical explanation: missing data can affect an estimated response percentage if missingness is associated with the unobserved outcome. Different assumptions about missing outcomes can lead to different estimates, so clear definitions of the analysis population, endpoint availability, and missing-data handling are important. Here, the listed arm sizes and percentages alone do not reveal the missing-data rules or confirm whether the analysis included every participant expected under a particular missing-data convention.

Part B is explicitly excluded because it was terminated before enrollment. Thus, the posted primary findings concern the treated, randomized Part A population only. The registry record does not report whether any planned analyses were changed after termination or whether the termination altered analysis plans.

11. Safety Results

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

Deaths

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: bone cyst (7.7%), hepatocellular carcinoma (2.9%), hydrocephalus (2.9%), deep vein thrombosis (2.9%), pancreatitis (2.8%).

The posted safety counts are reported separately for each Part A arm. Serious adverse events affected 3 of 35 participants in the prior sofosbuvir/ledipasvir failure arm receiving ribavirin, 4 of 36 in the corresponding arm without ribavirin, none of 9 in the prior grazoprevir/elbasvir failure arm receiving ribavirin, and 1 of 13 in the corresponding arm without ribavirin. Deaths were reported as 0 in each of the four arms. These are counts for the listed groups; they are not comparative estimates of treatment risk.

Other adverse events affected 29 of 35, 25 of 36, 9 of 9, and 12 of 13 participants in those same respective arms. The registry also lists serious adverse event terms and percentages: bone cyst, 7.7%; hepatocellular carcinoma, 2.9%; hydrocephalus, 2.9%; deep vein thrombosis, 2.9%; pancreatitis, 2.8%; and chest pain, 2.8%. The record does not make clear in the posted term list how the percentages map to individual arms or whether they refer to participants or event occurrences, so they should be read as listed rather than assigned to a particular group.

General statistical explanation: adverse-event counts describe events observed during the study and do not, without a suitable comparison and further context, establish causation. The registry record does not report the adverse-event collection window, detailed definitions, exposure-adjusted rates, or a formal safety comparison. The listed counts and terms therefore provide a descriptive safety account, not a complete estimate of comparative risk.

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

The posted primary results show that SVR12 percentages were high in each of the four analyzed Part A arms. The registry gives arm-level estimates from 97.1% to 100.0%, with 95% confidence intervals that differ in width. Those intervals are especially broad in the smaller prior grazoprevir/elbasvir groups. The estimates describe the outcomes among the randomized Part A participants who received at least one dose, under the endpoint definition and follow-up timing specified in the registry.

The result does not establish that adding ribavirin improves or worsens the outcome, that one treatment duration is better than another, or that the regimens are equivalent. The registry does not report a direct comparison between arms, an estimate of a difference, or a non-inferiority or equivalence analysis. Comparing the displayed percentages informally would not account for uncertainty or the different prior-treatment histories and group sizes.

These findings also do not answer the planned question for Part B. Part B was terminated before enrollment, so no outcome result is posted for its broader group of prior-treatment histories and genotypes. Nor do the SVR12 estimates describe outcomes beyond the stated follow-up point, all aspects of safety, or effects in people outside the analyzed Part A population.

General statistical explanation: evidence about an endpoint is strongest when the outcome definition, analysis population, missing-data approach, and planned comparison are all clear. The registry identifies the endpoint and analysis population, but does not report the detailed analysis plan, missing-data handling, or comparative tests. These absences limit the conclusions that can be drawn from the percentages. The posted results are informative as descriptive response estimates, but they are not a substitute for a reported comparative analysis or a complete account of longer-term outcomes.

13. Why This Trial Matters Statistically

This trial illustrates why a high point estimate needs to be read with its confidence interval and the number of participants in its arm. All four posted percentages are near the upper boundary of the scale, yet their lower confidence limits differ substantially. The intervals in the two smaller prior grazoprevir/elbasvir groups extend down to 66.4% and 75.3%, despite point estimates of 100.0%. The data therefore communicate both a high observed percentage and uncertainty about the underlying response in those groups.

It also highlights the distinction between describing separate arms and estimating a randomized treatment effect. Randomization is a feature of the design, but the reported outcome is presented as four separate percentages. The registry does not provide the planned pairwise comparisons or a pooled effect estimate. In a multi-arm trial where prior-treatment history and treatment regimen vary across groups, a reader needs a clearly defined contrast to determine what the results say about a specific treatment choice. The arm estimates alone do not resolve that question.

The record’s termination and the absence of Part B enrollment further define the scope of the evidence. Results are available for the analyzed Part A population, while the broader planned Part B population has no posted primary outcome data. The registry does not explain why the study was terminated, so the reason and its implications for completeness cannot be assessed from the record.

General statistical lesson: endpoint interpretation depends not just on the numerical estimate, but on precision, the analysis population, missing-data procedures, and the comparison specified by the design. Here, the record makes the SVR12 definition and Part A population visible, but leaves important analytic details unreported. That combination makes careful, bounded interpretation essential.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary estimates apply to Part A participants who were randomized and received at least one dose of study treatment. This is not described as an analysis of every randomized participant irrespective of treatment exposure. The registry does not report the number of participants excluded from that population, the number with missing SVR12 measurements, or how missing results were handled. The impact of missingness therefore cannot be assessed.

Precision varies across arms, and the prior grazoprevir/elbasvir failure groups are small, with 9 and 13 participants. Their broad confidence intervals mean that the point estimates of 100.0% are not precise estimates of the underlying response. The record identifies 95% confidence intervals but not the method used to calculate them.

The registry posts no comparative treatment-effect estimate, no secondary outcome results, and no statistical analysis plan. It does not report the randomization method, allocation concealment, planned comparisons, adjustment for multiple testing, or interim analyses. Those details are not reported in the registry record. The open-label design is stated, but the record does not say whether endpoint assessment was blinded.

Part B was terminated before enrollment, restricting the posted findings to Part A. The registry status is terminated, but the reason for termination and its relationship to follow-up or analysis completion are not reported. The record also does not report the trial’s own sample-size justification. Accordingly, the posted results do not establish outcomes for Part B or provide a complete basis for assessing all planned analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy and Safety of Grazoprevir (+) Uprifosbuvir (+) Ruzasvir (MK-3682B) (MK-5172 + MK-3682 + MK-8408) Fixed Dose Combination in Chronic HCV Participants Failing Prior Antiviral Treatment (MK-3682-021) — NCT02613403.
• Registry record last updated 2024-05-22; status last verified 2024-05.
• Results first posted 2018-03-20.
• 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.

18. Record Summary

NCT02613403 was a phase II, randomized, open-label, parallel, multicenter trial of MK-3682B, with or without ribavirin, in chronic hepatitis C after prior antiviral treatment failure. The registry lists enrollment of 94 and status as terminated. Part A included four arms differentiated by prior treatment history, ribavirin use, and treatment duration. Part B was terminated before enrollment and was not analyzed.

The primary endpoint was SVR12, defined as HCV RNA below the assay LLOQ of 15 IU/mL 12 weeks after the final study dose. Posted Part A estimates ranged from 97.1% to 100.0%, with arm-specific 95% confidence intervals. The results are descriptive and do not include a reported direct comparison between arms. Safety counts are also posted by arm, including zero reported deaths in each group. Missing-data handling, multiplicity procedures, detailed analysis methods, and the reason for termination are not reported in the registry record.