A Study to Evaluate Long-term Outcomes Following Treatment With ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate Long-term Outcomes Following Treatment With ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (NCT02219490), a na phase 3 study. The primary outcome is All-Cause Death: Time to Event.

2. Clinical Question

The clinical question is therefore descriptive: what long-term mortality experience was recorded among participants who received the study regimen, and how was that experience estimated over follow-up? The registry defines time to death from the first day of study-drug dosing to the date of death. Deaths were included regardless of whether participants were still taking study drug or had stopped it. Participants without a recorded death were censored at their last available clinical-outcome assessment; participants without a post-baseline assessment were censored on the first dosing day.

The endpoint’s pre-specified analysis pooled data from TOPAZ-I and TOPAZ-II. That pooled analysis population is not the same as the TOPAZ-I enrollment alone. The registry record does not report a randomized treatment contrast or an independent comparator for the long-term mortality question.

3. Trial Design

TOPAZ-I (NCT02219490) was a Phase 3, open-label, multicenter, single-group study sponsored by AbbVie. The registry lists 1596 participants as enrolled, with the condition described as chronic hepatitis C virus genotype 1 infection. The study started on 2014-10-30, reached primary completion on 2021-05-13, and is listed as completed.

The evaluated treatment combined ABT-450/ritonavir/ABT-267 and ABT-333, with or without ribavirin. The intervention list names ABT-450/r/ABT-267, ABT-333, and ribavirin. The registry includes a regimen description for participants with HCV GT1b without cirrhosis: the three-drug combination was taken for 12 weeks, with the listed dose schedule. The available arm description is incomplete after its reference to participants with HCV, so the full set of participant-specific regimens and assignment rules is not reported in the registry record.

The record identifies no allocation and no masking. A single-group, open-label design is not a randomized comparison: it does not assign participants to treatment and control groups for a like-for-like contrast. Nor does the registry entry establish that every participant received the same ribavirin regimen. The treatment question is framed around the combination with or without ribavirin, but the available description does not fully explain how that distinction was determined.

The primary endpoint was all-cause death as a time-to-event outcome. Assessments were specified at post-treatment weeks 52, 104, 156, 208, and 260. The endpoint description says the primary analysis pooled participants from TOPAZ-I and companion study TOPAZ-II, provided they had received at least one dose of study drug. Thus the primary analysis population extends beyond the 1596 TOPAZ-I enrollees. Details of how the companion-study data were combined beyond that description are not reported in the registry record.

Secondary outcomes listed include change from baseline in FibroScan score by SVR12 status and the percentage of participants with sustained virologic response 12 weeks post-treatment. The record lists 8 outcome measures and 20 analyses. It does not report the protocol rationale for the design or the allocation and follow-up procedures in sufficient detail to reconstruct them.

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: Safety population: All participants enrolled in this study (M14-423; TOPAZ-I) who received at least one dose of study drug

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population: all enrolled participants in this study (TOPAZ-I; M14-423; ITT-I) and in companion study M14-422 (TOPAZ-II; NCT02167945; ITT-II) who received at least one 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: Safety population: All participants enrolled in this study (M14-423; TOPAZ-I) who received at least one dose of study drug

6. Primary Endpoint

The registry lists the primary outcome as All-Cause Death: Time to Event, measured over At Post-Treatment Weeks 52, 104, 156, 208, and 260.

The primary endpoint is time to all-cause death. It measures the interval from the first day of study-drug dosing to the date of death and includes deaths whether they occurred during treatment or after treatment had been discontinued. Participants who did not die were censored at their last available clinical-outcome assessment. If a participant had no post-baseline assessment, censoring was assigned on the first day of study-drug dosing.

Time-to-event analysis is used when both whether an event occurred and when it occurred are relevant. It can incorporate information from participants who have not experienced the event by their last recorded assessment, rather than treating their follow-up as if it were a death. In general, censoring indicates that the event time was not observed during the available follow-up; it does not establish what happened after the last recorded assessment.

The registry states that event-free survival rates were estimated using Kaplan-Meier methodology and that incidence estimates are presented with 95% confidence intervals. In general, a confidence interval communicates uncertainty around an estimate: it indicates a range of values compatible with the data and the method’s assumptions, rather than a guarantee about the true value. The actual mortality estimates and confidence intervals are not reported in the registry record, so the size and precision of the posted primary endpoint results cannot be assessed from the record summary alone.

All-cause death captures death from any cause rather than attributing each death to a particular disease or treatment. The endpoint description also specifies that the analysis pooled eligible participants from TOPAZ-I and TOPAZ-II. It is therefore a long-term descriptive endpoint across the pooled analysis population, not a direct estimate of a treatment effect versus a concurrent control group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help clarify what the registry’s endpoint definition can establish. The most important distinction is between a time-to-event estimate and a simple event count. A count says how many events were recorded in a defined group. A time-to-event analysis also uses when events occurred and how long participants were followed before an event or censoring.

What does censoring mean?

In general, censoring occurs when follow-up ends before the event of interest is observed. For the all-cause-death endpoint, the registry specifies censoring at the last available assessment of clinical outcomes for participants who did not die. For a participant with no post-baseline assessment, it specifies censoring on the first day of study-drug dosing. Censoring does not mean that the participant was known to remain alive indefinitely; it means that the analysis stops contributing observed follow-up at the stated time.

Time-to-event methods can use the observed time before censoring without treating censored participants as if they had experienced the endpoint. In general, this requires assumptions about how censoring relates to the chance of the event. If participants with different underlying risks have systematically different follow-up, estimates may be affected. The registry gives the censoring rules but does not report the extent or pattern of censoring, or diagnostic checks of the assumptions.

How does Kaplan-Meier estimation work?

In general, Kaplan-Meier estimation builds an event-free survival curve over follow-up. At each observed event time, it updates the estimated probability of remaining event-free, using the participants still under observation at that point. Participants contribute information while they are observed; after censoring, they no longer contribute to later risk sets. This method is useful when follow-up times differ and some participants have not experienced the event when observation ends.

The registry says event-free survival rates were estimated using Kaplan-Meier methodology, with incidence estimates presented alongside 95% confidence intervals. The confidence interval expresses uncertainty in the estimate under the method’s assumptions. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. The numerical estimates and intervals are not reported in the registry record, so their precision cannot be evaluated from the stated method alone.

Why use time to all-cause death?

All-cause death is an endpoint that counts death regardless of cause. In general, this avoids requiring a cause-of-death classification for the endpoint definition. The registry’s definition includes deaths during study-drug use as well as deaths after discontinuation. That rule keeps the endpoint tied to the participant’s follow-up rather than limiting events to the period of active treatment.

The endpoint was assessed at post-treatment weeks 52, 104, 156, 208, and 260. These are specified assessment time points; they do not, by themselves, show how many participants remained under observation at each point or how many deaths had occurred by then. The registry does not report those details in the record summary.

What does pooling the studies mean?

The pre-specified analysis pooled data from TOPAZ-I and the companion study TOPAZ-II. Its population included enrolled participants in both studies who received at least one dose of study drug. Pooling combines observations across studies for the stated endpoint; it does not create a randomized control group. In general, interpretation of pooled data also depends on whether the studies and their participant populations are sufficiently compatible for the analysis. The registry record identifies the pooled population but does not report the detailed rationale, stratification approach, or study-level checks used for pooling.

It is important to keep the pooled mortality analysis distinct from TOPAZ-I’s enrollment and safety group. The TOPAZ-I enrollment is 1596. The safety group also lists 1596 participants at risk, whereas the primary endpoint definition includes eligible participants from the companion study as well. The record does not give the pooled total or the number of endpoint events in that pooled population.

What can a single-group design estimate?

In general, a single-group study can describe outcomes among participants who receive the studied regimen. It does not offer the randomized, concurrent comparison needed to separate treatment effects from other influences. Differences in health status, follow-up, other treatment, or changes over time can affect observed outcomes. Because TOPAZ-I is listed as single-group, with allocation recorded as none and masking as none, its design does not support a like-for-like randomized treatment contrast.

Statistical significance, had a comparative test been reported, would not resolve the design limitation on its own. A comparison requires an appropriate contrast and assumptions about how the groups came to differ. No such randomized comparison is reported for this study. The registry record also does not report a protocol-based sample-size justification, interim analyses, or a detailed statistical analysis plan. Those elements should not be inferred from the fact that the study is Phase 3 or from the endpoint method listed.

Any sample-size planning illustration based on an observed effect is a planning exercise, not observed power and not evidence that the original design had that power. In general, a planned sample size depends on the assumed effect, variability or event rate, significance level, allocation, and analysis method. The registry record does not report its own sample-size justification. The stated planning assumptions should therefore be read as illustrative rather than as a description of the trial’s design rationale.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and 20 analyses, including the primary time-to-all-cause-death endpoint and secondary outcomes related to FibroScan score and sustained virologic response. When a study examines multiple endpoints, time points, or analyses, the chance of finding at least one apparently notable result can increase. In general, multiplicity procedures can control that risk, but the choice depends on which outcomes and comparisons were planned and how they were prioritized. The registry record does not report a multiplicity adjustment strategy or a hierarchy for interpreting the listed analyses.

The primary endpoint description identifies assessments at post-treatment weeks 52, 104, 156, 208, and 260 and states that Kaplan-Meier methodology was used. It does not report whether the assessment time points were treated as separate inferential tests, how confidence intervals were constructed, or whether any interim analyses were planned. Those details are not reported in the registry record and should not be assumed.

Missing follow-up is addressed in the endpoint definition through censoring at the last available clinical-outcome assessment, or on the first dosing day for participants without a post-baseline assessment. In general, censoring retains observed follow-up but does not recover unobserved outcomes after follow-up ends. Its interpretation depends on the censoring process and the analysis assumptions. The registry record does not report the amount of missing follow-up, reasons for loss to follow-up, sensitivity analyses, or additional missing-data procedures.

The primary endpoint population was defined as eligible participants in TOPAZ-I and TOPAZ-II who received at least one dose of study drug. This is an analysis-population definition, not a complete account of who contributed at each follow-up time. The registry record does not report participant counts at each time point or describe how exclusions and unavailable assessments were handled beyond the stated censoring rules.

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: pneumonia (0.1%), hepatocellular carcinoma (0.1%), anaemia (0.1%), angina unstable (0.1%), palpitations (0.1%).

The registry lists one safety group titled ABT-450/r/ABT-267 plus ABT-333 with or without ribavirin. It reports 1596 participants at risk for serious adverse events and 40 participants affected. For other adverse events, the group also lists 1596 at risk and 805 affected. These are separate descriptive categories in the registry record; they should not be added together because a participant may have experienced events in more than one category.

The listed serious adverse-event terms are pneumonia, hepatocellular carcinoma, anaemia, unstable angina, palpitations, and upper abdominal pain, each reported as 0.1%. These entries identify selected terms and their reported percentages; they do not provide a complete account of event severity, timing, recurrence, or treatment attribution. The record lists 28 deaths in the safety group, but that count is not the same as the pooled Kaplan-Meier primary endpoint estimate.

In general, adverse-event counts describe what was recorded in the observed group. Without a randomized comparator, they cannot establish how those counts compare with another treatment or what would have occurred without the study regimen. They also do not establish that a particular event was caused by treatment. The registry record does not report additional detail in this safety summary to support those causal or comparative judgments.

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

The record establishes that TOPAZ-I evaluated long-term outcomes following treatment with ABT-450/ritonavir/ABT-267 and ABT-333, with or without ribavirin, in adults with genotype 1 chronic hepatitis C virus infection. It was an open-label, Phase 3, single-group study with 1596 enrolled participants. The primary endpoint was time to all-cause death, with follow-up assessments specified through post-treatment week 260 and estimation by Kaplan-Meier methodology.

The record also reports safety counts for the treatment group: 40 participants with serious adverse events, 805 with other adverse events, and 28 deaths among 1596 at risk. These are descriptive counts. They do not supply a randomized comparison, nor do they show whether the event counts differ from those under another treatment or no study treatment. The serious-event terms listed at 0.1% each provide selected event descriptions but do not establish causation.

The mortality endpoint has an additional population distinction: its pre-specified analysis pooled eligible participants from TOPAZ-I and TOPAZ-II. The safety group and enrollment figures refer to TOPAZ-I, while the mortality analysis as defined is broader. The registry record does not report the pooled mortality estimates or their confidence intervals in the information summarized for this analysis. Consequently, the observed magnitude and precision of the primary endpoint cannot be evaluated from the record summary.

What the study design does not establish is a causal effect of treatment relative to a control. There is no randomized comparator group, and the registry identifies no allocation. The results therefore should not be read as proving that the regimen did or did not alter mortality, or as a comparison against another regimen. A single-group study describes outcomes in its observed participants but cannot separate treatment effects from participant characteristics, other care, or other influences.

The registry lists secondary outcomes concerning FibroScan change and sustained virologic response, but their numerical results are not reported in the registry record. Their listing alone does not establish the direction, size, or precision of any finding. The record also does not report the study’s sample-size justification, detailed statistical plan, multiplicity approach, or extent of missing follow-up. These omissions limit assessment of how the planned analyses were justified and how robust the estimates may be.

13. Why This Trial Matters Statistically

This study illustrates why the endpoint definition and the study design must be read together. A time-to-event endpoint can describe both the occurrence and timing of death while accounting for participants whose follow-up ends before an event is recorded. Kaplan-Meier estimation is a standard way to represent event-free survival under such follow-up, and confidence intervals are intended to communicate the uncertainty around those estimates.

But a sound method for estimating outcomes within a group does not supply a missing comparison. TOPAZ-I is identified as a single-group study with no allocation and no masking. Its primary endpoint analysis also pooled eligible participants from the companion TOPAZ-II study. Those features define what population is described and prevent treating the endpoint as a randomized contrast between treatment and control.

The record also demonstrates why event counts and time-to-event estimates are not interchangeable. The safety summary lists 28 deaths for the TOPAZ-I group, while the primary endpoint is defined for a pooled population and is estimated using follow-up time and censoring. A simple count cannot convey the same information as a time-to-event curve or its uncertainty. The numerical primary endpoint estimates themselves are not reported in the registry record, so their interpretation is limited.

Finally, the listed adverse events are descriptive. Reporting counts and selected terms helps characterize what was recorded, but a single treatment group cannot show whether those events were more or less frequent than under an alternative. The statistical importance of this record lies in distinguishing descriptive long-term follow-up from comparative evidence, and in recognizing that endpoint methods, population definitions, censoring, and design all shape what conclusions an analysis can support.

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.

Several limitations are specific to the registry information for this study. First, the primary endpoint is defined and its analysis method is named, but the numerical event-free survival estimates and 95% confidence intervals are not reported in the registry record. Without them, the magnitude and precision of the reported mortality analysis cannot be assessed from this record summary.

Second, the primary endpoint population includes eligible participants from TOPAZ-I and TOPAZ-II, while the enrollment and safety group described for TOPAZ-I list 1596 participants. The pooled total and the number of deaths contributing to that endpoint analysis are not reported in the registry record. The 28 deaths in the safety group should not be substituted for a pooled time-to-event result.

Third, the open-label, single-group design provides no randomized control comparison. This limits causal interpretation of mortality and adverse-event counts. The record does not describe a concurrent control group for the endpoint, and its design information explicitly indicates no allocation.

Fourth, the arm description is incomplete after referring to participants with HCV. Although one regimen description is given for participants with HCV GT1b without cirrhosis, the full regimen details for all participant groups and the rules determining treatment with or without ribavirin are not reported in the registry record.

Finally, the registry does not report the sample-size justification, detailed statistical analysis plan, multiplicity procedures, interim analyses, counts at each follow-up time, or the amount and reasons for missing follow-up. These omissions make it difficult to evaluate the planning rationale, the full analysis process, and the sensitivity of estimates to incomplete observation. The registry lists secondary outcomes, but their numerical results are also not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate Long-term Outcomes Following Treatment With ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection — NCT02219490.
• Registry record last updated 2023-04-07; status last verified 2022-06.
• Results first posted 2023-04-07.
• 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

TOPAZ-I (NCT02219490) was a completed, open-label, multicenter, Phase 3, single-group study sponsored by AbbVie. It enrolled 1596 adults with chronic hepatitis C virus genotype 1 infection. The evaluated regimen included ABT-450/ritonavir/ABT-267 and ABT-333, with or without ribavirin. The study started on 2014-10-30 and reached primary completion on 2021-05-13.

The primary endpoint was time to all-cause death, with assessments at post-treatment weeks 52, 104, 156, 208, and 260. The stated analysis used Kaplan-Meier methodology and pooled eligible participants from TOPAZ-I and TOPAZ-II. The registry record does not report the numerical primary endpoint estimates or confidence intervals in the information. The safety group lists 40 participants with serious adverse events, 805 with other adverse events, and 28 deaths among 1596 at risk. The study has no randomized comparator, so these findings are descriptive rather than a like-for-like treatment comparison.