Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection (NCT02249182), a non-randomized phase 2 study. The primary outcome is For Participants in the PK Lead-in Phase, Pharmacokinetic (PK) Parameter: AUCtau of GS-331007 (Metabolite of SOF), LDV, and SOF.

2. Clinical Question

In practical terms, the study was designed to examine pediatric dosing and drug exposure before evaluating longer treatment courses across age cohorts. It also recorded treatment-phase outcomes such as sustained virologic response and viral breakthrough or relapse. Those outcomes are listed as secondary measures, but their numerical results are not reported in the registry record. The record therefore supports a description of the questions and design, not an assessment of the magnitude or precision of treatment-phase antiviral outcomes.

3. Trial Design

This was a phase 2, nonrandomized, open-label, multicenter, parallel study of ledipasvir/sofosbuvir, with or without ribavirin, in pediatric participants with chronic hepatitis C virus infection. The registry reports enrollment of 226 participants and a completed status. Its recorded start date is 2014-11-05 and its primary completion date is 2018-06-15. These dates describe the study record; they do not provide the timing of individual participant follow-up or the timing of specific analyses.

The design had a pharmacokinetic lead-in phase and a treatment phase. In the lead-in, the stated objective was to assess steady-state pharmacokinetics and confirm pediatric dosing. It also assessed safety, tolerability, and antiviral activity during 10 days of dosing. The treatment phase was to begin by age cohort after confirmation of age-appropriate doses. Participants in the lead-in were to roll over directly into treatment without interruption of study drug administration.

The treatment phase evaluated ledipasvir/sofosbuvir, with or without ribavirin, for 12 or 24 weeks. Cohorts were described for ages 12 to < 18 years, 6 to < 12 years, and 3 to < 6 years. The registry gives different tablet or granule formulations according to age, weight, and swallowability assessment. It also states that treatment duration depended on hepatitis C virus genotype and prior treatment experience. The full allocation of participants to treatment regimens and the rules used to assign them are not reported in the registry record.

Because allocation was nonrandomized and masking was absent, cohort differences cannot be interpreted as randomized treatment effects. Age, formulation, duration, and ribavirin use may distinguish cohorts as well as the assigned regimen. The record does not describe a concurrent randomized comparator. Screening included placebo tablets matching the study formulation to assess ability to swallow, but that screening procedure does not establish a placebo-controlled treatment comparison.

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: 240 participants were screened.

PK Lead-In Phase

Treatment Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intensive PK Analysis Set included all participants in the PK lead-in phase who received at least 1 dose of study drug and for whom at least 1 nonmissing PK concentration value, during the intensive sampling period, was reported by the PK laboratory.

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 Analysis Set included all participants who were enrolled into the study and received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as For Participants in the PK Lead-in Phase, Pharmacokinetic (PK) Parameter: AUCtau of GS-331007 (Metabolite of SOF), LDV, and SOF, measured over Cohorts 1 and 2 (6 to < 18 years of age): predose, 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose on Day 10; Cohort 3 (3 to < 6 years of age): predose, 0.5, 2, 4, 8, and 12 hours postdose on Day 10.

The primary endpoint is the pharmacokinetic parameter AUCtau for GS-331007, ledipasvir, and sofosbuvir in participants in the pharmacokinetic lead-in phase. AUCtau represents drug concentration over time across the dosing interval: it is the area under the concentration-time curve during that interval. The endpoint is expressed in h*ng/mL, with the stated summary measure being the mean and the stated measure of dispersion being the standard deviation.

Pharmacokinetic measurements help characterize how much drug exposure occurs over time after dosing. In a pediatric dose-confirmation study, exposure information can inform whether age-appropriate formulations and doses produce the intended drug levels. That is a general role of pharmacokinetic endpoints; it does not by itself establish clinical benefit or safety.

Sampling took place on Day 10. For cohorts 1 and 2, described as ages 6 to < 18 years, the scheduled times were predose and 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose. For cohort 3, ages 3 to < 6 years, sampling was predose and 0.5, 2, 4, 8, and 12 hours postdose. The intensive pharmacokinetic analysis set included lead-in participants who received at least one dose and had at least one nonmissing concentration value during intensive sampling reported by the pharmacokinetic laboratory.

The registry record does not report the endpoint’s mean or standard deviation, nor the number analyzed for each drug or cohort. Those numerical results and any associated uncertainty estimates are therefore not available in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is AUCtau, a continuous pharmacokinetic endpoint. A continuous measure can take values across a scale rather than being limited to event counts or categories. The registry specifies the mean as the summary and standard deviation as the measure of dispersion. The mean describes the central level of the measured exposure in the analyzed participants. The standard deviation describes how spread out individual measurements are around that mean. It is not a confidence interval and does not, by itself, express uncertainty about the mean.

What does AUCtau represent?

In general, an area under a concentration-time curve combines concentration and time across a specified interval. AUCtau is defined in the record as the area under the concentration-versus-time curve over the dosing interval. Its unit, h*ng/mL, reflects concentration measured over time. The registry lists separate parameters for GS-331007, ledipasvir, and sofosbuvir. Because the observed values are not reported in the registry record, their relative levels, variability, and precision cannot be interpreted from the record.

Why are sampling times and analysis populations important?

Pharmacokinetic estimates depend on when concentrations are sampled and which participants contribute usable measurements. The record specifies different intensive sampling schedules for the younger cohort and the two older cohorts. It defines the intensive pharmacokinetic analysis set as lead-in participants who received at least one dose and had at least one nonmissing concentration value during intensive sampling reported by the pharmacokinetic laboratory. This definition is narrower than simply counting everyone enrolled or everyone assigned to a treatment cohort. The number in the analysis set is not reported in the registry record.

In general, missing concentration observations can affect the amount of information available and may affect an estimate if the reason for missingness is related to drug exposure or participant characteristics. The record does not describe how incomplete sampling schedules were handled, whether concentration values were excluded under additional rules, or how pharmacokinetic parameters were estimated from the samples. Those analytic details are not reported in the registry record, so the method’s sensitivity to incomplete data cannot be assessed.

How should the safety counts be read?

Safety event counts are descriptive summaries. They identify the number of participants at risk in each listed cohort and the number reported with serious or other adverse events. They are not randomized comparisons, and the cohort sizes and regimens differ. In general, a count from a small cohort is particularly limited as a guide to the range of possible event experience; a zero count does not prove that an event cannot occur. The registry does not provide uncertainty intervals or a detailed account of how adverse events were collected and coded.

What does nonrandomized allocation mean?

In a randomized trial, assignment by chance can make groups more comparable on average, including for factors that were not measured. This study is described as nonrandomized and open-label. In general, nonrandomized groups can differ in participant characteristics, treatment selection, or other factors that influence outcomes. Open-label means masking was absent, so participants and study personnel were not blinded to treatment assignment. These features do not invalidate descriptive results, but they limit causal interpretation of differences between cohorts. The registry specifically cautions that the arms are not a like-for-like control comparison.

The parallel model indicates that the study is described as having groups followed under their assigned regimens rather than a crossover structure. The registry also describes a lead-in phase followed by a treatment phase, with lead-in participants rolling over into treatment without interruption. It does not report further detail about the timing or handling of the transition in the analyses. The arm descriptions indicate age-based cohorts and treatment regimens, but the complete assignment process is not reported in the registry record.

What can planning calculations tell readers?

In general, a sample-size calculation uses assumptions about the effect to detect, variability, significance level, allocation, and statistical method. The planning illustration associated with the study is described as using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power. They do not show the probability that the completed study detected an effect, and they do not replace the trial’s actual estimates or uncertainty intervals. No numerical sample-size planning values are reported in the registry record.

For time-to-event calculations, the stated convention is a total number of events; for other calculations, it is participants per arm. These conventions describe how a planning quantity would be expressed, not how many participants were analyzed in this study. The record does not report the assumptions used in the original trial design or a sample-size justification for the trial itself. It also does not report interim analyses or the detailed statistical analysis plan. In general, those details matter because they clarify what comparisons were planned, how uncertainty was quantified, and whether analyses were adjusted for multiple outcomes.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 20 outcome measures and 9 analyses. The primary endpoint is a pharmacokinetic measure, while the listed secondary outcomes include several treatment-phase measures, among them sustained virologic response at 4, 12, and 24 weeks after discontinuation, viral breakthrough, viral relapse, and change from baseline in hepatitis C virus RNA. Examining multiple outcomes creates a general multiplicity issue: when many hypotheses are tested, the chance of at least one apparently notable finding can increase unless the analysis plan addresses that issue.

The registry record does not report whether the analyses used a multiplicity adjustment, how the primary and secondary outcomes were ordered for inference, or which outcome comparisons were designated confirmatory. It does not report an interim-analysis plan or stopping boundaries. These details are not reported in the registry record, so it is not possible to determine how the number of outcomes and analyses was handled statistically.

Missing-data methods are also not described in sufficient detail. The primary pharmacokinetic population requires at least one nonmissing concentration result during intensive sampling, but the number meeting that definition and the handling of incomplete profiles are not reported. For treatment-phase outcomes, the registry lists measures but does not state the analysis population, denominators, or rules for missing follow-up measurements. The handling of participants who discontinued treatment or lacked post-treatment viral measurements is not reported in the registry record.

The record therefore does not support a detailed appraisal of multiplicity control, missing-data assumptions, or the analysis populations used for each treatment outcome. In general, these choices can affect both the estimate and its uncertainty. The listed outcomes should not be read as though every one was analyzed with the same denominator or inferential status.

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: abdominal pain (1.1%), gastroenteritis (1.1%), tooth abscess (1.1%).

The serious adverse event counts are reported by treatment cohort. In the 12 to < 18 years old, ledipasvir/sofosbuvir 12-week group, 0 of 100 participants had a reported serious adverse event. In the 6 to < 12 years old, ledipasvir/sofosbuvir 12-week group, 1 of 89 did. In the 6 to < 12 years old, ledipasvir/sofosbuvir 24-week group, 0 of 1 did; in the corresponding 24-week group with ribavirin, 0 of 2 did; and in the 3 to < 6 years old, ledipasvir/sofosbuvir 12-week group, 0 of 34 did. The record reports 0 deaths in each listed group.

The registry lists abdominal pain, gastroenteritis, and tooth abscess among the top serious adverse event terms, each at 1.1%. It does not provide enough detail in these figures to connect each term to a specific cohort or to establish how event counts relate to individual participants. These percentages should therefore be read as reported terms, not as comparative risks between regimens.

In general, serious-event counts are descriptive and do not establish that a treatment caused or prevented an event. A zero count in a cohort, especially one with few participants, does not show that the event is impossible. The figures do not describe all adverse events, their duration, severity grading beyond the serious classification, or the complete safety analysis population. Those details are not reported in the registry record.

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

The registry record describes a pediatric study that was intended to characterize drug exposure, confirm age-appropriate dosing, and assess safety and antiviral outcomes during treatment. It identifies AUCtau as the primary endpoint in the pharmacokinetic lead-in phase and provides the scheduled sampling times and definition of the intensive analysis set. It also lists treatment-phase outcomes and reports serious adverse event counts for five cohorts.

What the record does not establish is the observed pharmacokinetic exposure or the numerical antiviral response in the treatment phase. The means and standard deviations for AUCtau are not reported in the registry record. Numerical results for sustained virologic response, viral breakthrough, viral relapse, and change in hepatitis C virus RNA are also not reported. Consequently, the record does not permit a judgment about the size, consistency, or precision of those outcomes.

The design further limits comparisons between cohorts. Assignment was nonrandomized, masking was absent, and the groups varied in age, treatment duration, and use of ribavirin. The registry states that the arms are not a like-for-like control comparison. Apparent differences across such groups would not, by themselves, isolate the effect of a regimen or treatment duration.

In general, a completed study and an enrollment total do not imply that every planned result is available in the registry. Interpretation requires the actual estimates, denominators, uncertainty measures, and analysis methods. Without those details, the defensible account is limited to what was measured, how the study was structured, and the safety counts that are reported. No clinical recommendation follows from these registry entries alone.

13. Why This Trial Matters Statistically

This study raises statistical questions that are common in pediatric pharmacology. Children across broad age bands may require different formulations and dose levels, and drug exposure cannot be inferred solely from the nominal regimen. A pharmacokinetic lead-in can characterize exposure using concentration measurements over time and can support dose confirmation before treatment-phase evaluation. The study’s primary endpoint, AUCtau, directly reflects that exposure-focused objective.

The design also illustrates the difference between a pharmacokinetic endpoint and a clinical or virologic outcome. Drug concentration measurements address exposure; sustained virologic response and changes in viral RNA address antiviral outcomes. Safety events address a separate dimension. A study may assess all of these, but each answers a different question and requires its own result estimates and analysis population. Here, the registry describes these outcome categories but does not report the numerical primary endpoint or treatment-phase efficacy results.

Age-based cohorts, multiple formulations, differing treatment durations, and ribavirin use make interpretation more complex. Because allocation was nonrandomized, comparisons between cohorts can reflect differences in more than the regimen itself. The design is therefore useful to describe as a set of pediatric cohorts and assessments, not as a randomized test of one treatment against another.

Statistically, the record underscores why outcome definitions, denominators, missing-data rules, and uncertainty estimates matter. Without them, enrollment and outcome labels alone cannot show how precise or comparable the results are. The record’s limited safety counts can be described, but they do not answer the broader efficacy question.

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 principal limitation for interpreting results is that numerical primary-endpoint results are not reported in the registry record. The listed mean and standard deviation therefore cannot be reviewed, and there is no reported confidence interval for the pharmacokinetic estimate. Numerical treatment-phase results for the listed secondary outcomes are also absent. This prevents assessment of effect size, variability, and precision for the principal antiviral outcomes.

The study is nonrandomized and open-label. Cohorts are organized by age and differ in treatment regimen, duration, and ribavirin use. The record explicitly cautions that the arms are not a like-for-like control comparison. Consequently, between-cohort differences would be difficult to interpret as effects of the regimen alone. The number enrolled overall does not establish the number analyzed in each cohort or for each outcome.

The registry identifies a pharmacokinetic analysis population but does not report its size or describe the complete handling of missing concentration data. It also does not report treatment-outcome analysis populations, missing-data rules, multiplicity procedures, interim analyses, or the detailed statistical plan. These omissions limit evaluation of how estimates were produced and how robust they may be.

The reported serious adverse event figures cover the listed groups, but the record does not provide a complete account of event ascertainment, coding, follow-up, or uncertainty. Some listed cohorts are very small, so their event counts offer limited descriptive information. The safety figures should not be treated as comparative evidence between regimens.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children With Chronic HCV-Infection — NCT02249182.
• Registry record last updated 2020-03-02; status last verified 2019-03.
• Results first posted 2019-04-24.
• 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

The registry record describes NCT02249182, a completed phase 2, nonrandomized, open-label, multicenter, parallel study of ledipasvir/sofosbuvir with or without ribavirin in children and adolescents with chronic hepatitis C virus infection. Enrollment was 226. The study included a pharmacokinetic lead-in and a treatment phase, with treatment courses described as 12 or 24 weeks across age-based cohorts.

The primary endpoint was AUCtau for GS-331007, ledipasvir, and sofosbuvir during the lead-in phase. The record provides its definition, units, sampling schedule, and analysis population criteria, but not numerical endpoint results. Treatment-phase secondary outcomes include sustained virologic response, viral breakthrough, viral relapse, and change in viral RNA; numerical results for these outcomes are not reported in the registry record.

Serious adverse event counts are reported for five treatment groups, with 0 deaths in each. The design does not support like-for-like comparisons between arms. Detailed statistical procedures, missing-data methods, and multiplicity handling are not reported in the registry record.