Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection (NCT02219685), a randomized phase 2 study. The primary outcome is Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: NAA + NAAG.

2. Clinical Question

The registry describes cerebral metabolism and neurocognition as primary objectives, and identifies the NAA + NAAG MRS ratio as the primary outcome measure. It does not provide a numerical outcome result, an estimate of change, or a treatment-group comparison for this endpoint. The record therefore does not establish the size or precision of any observed change, or whether the measure differed between groups.

The clinical question is broader than the primary endpoint alone: the study also listed sustained virologic response, neurocognitive domains, and health-related quality of life as secondary outcomes. Those outcomes concern different aspects of participants’ status and were assessed at different time points. The registry record does not report their results in the registry record for this analysis.

3. Trial Design

This was a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel-group study. The registry lists enrollment of 40 participants. During the blinded treatment phase, participants were randomized in a 2:1 allocation to LDV/SOF FDC or placebo, with treatment planned for 12 weeks. Treatment-naive and treatment-experienced adults with chronic genotype 1 HCV infection were eligible populations described by the study record.

The placebo comparison was limited to the blinded phase. After unblinding at the Posttreatment Week 4 visit, participants from the placebo group were offered 12 weeks of open-label LDV/SOF FDC. This later treatment period is a separate exposure phase: those participants had first received placebo and then had the opportunity to receive active treatment. The record lists 14 participants at risk in this open-label phase.

The primary endpoint was change from baseline in the NAA + NAAG MRS metabolic ratio at 4 weeks after discontinuation of therapy. The specified analysis population included randomized participants who received at least 1 dose. The registry describes MRS measurements in three brain areas and a ratio using creatine as the control metabolite. The endpoint is reported as a mean with standard deviation, but numerical values are not reported in the registry record.

The record lists 22 outcome measures and 14 analyses. Secondary outcomes included SVR at 4, 12, and 24 weeks after therapy discontinuation; changes in memory, attention, executive function, and motor measures; and physical and mental components of health-related quality of life. The registry record does not report further details of randomization procedures, allocation concealment, the statistical analysis plan, or how the study’s single-center setting was handled analytically.

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: 54 participants were screened.

Blinded Treatment Phase

Reasons for not completing this period:

Open-Label (After Posttreatment Week 4)

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set: participants who were randomized into the study and 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: Safety Analysis Set: participants who were randomized into the study and received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Metabolic Ratio at 4 Weeks After Discontinuation of Therapy: NAA + NAAG, measured over Baseline; Posttreatment Week 4.

The primary endpoint is change from baseline in the magnetic resonance spectroscopy metabolic ratio for NAA + NAAG at 4 weeks after discontinuation of therapy. NAA refers to N-acetylaspartate, and NAAG to N-acetylaspartylglutamate. The registry describes the signal as a cerebral metabolic measure assessed by MRS in the basal ganglia, frontal cortex, and dorsolateral prefrontal cortex. Creatine served as the control metabolite, so results are expressed as a ratio rather than in physical units.

In general, MRS measures chemical signals from tissue and can be used to characterize aspects of cerebral metabolism without treating the measurement as a direct clinical outcome. The use of a ratio places the signal of interest in relation to the control metabolite. A change in that ratio is therefore a change in the measured metabolic signal relative to creatine; its clinical interpretation depends on the study context and on the reliability and meaning of the measurement.

The endpoint’s timing is important: it concerns the assessment 4 weeks after treatment discontinuation, not the value during treatment. The registry identifies a mean and standard deviation as the summary approach. It does not report the observed means, standard deviations, changes, uncertainty intervals, or a comparison between randomized groups. The endpoint definition alone cannot show whether a change occurred or how precisely it was estimated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins by identifying what was measured, when it was measured, and which participants contributed to the analysis. For this trial, the primary measure was the NAA + NAAG MRS metabolic ratio, expressed relative to creatine, and the stated time point was 4 weeks after therapy discontinuation. The stated analysis population was the Full Analysis Set, defined as randomized participants who received at least 1 dose of study drug. The number actually analyzed for the endpoint is not reported in the registry record.

What does a mean and standard deviation describe?

A mean describes the center of a set of measurements. A standard deviation describes how spread out individual measurements are around that mean. Together, these summaries can help characterize a continuous outcome, but they do not by themselves provide the uncertainty around a group comparison. A standard deviation reflects variation among observations; a confidence interval for an estimate reflects uncertainty in that estimate under the analysis assumptions. The registry specifies mean and standard deviation for the primary outcome but does not report their values.

The endpoint is a change from baseline, which requires a baseline measure and a later measure for interpretation. A change score describes how the measured value differs from its starting value for the analysis population or group. A comparison of changes between randomized groups answers a different question from describing change in either group alone. The registry record names the change-from-baseline endpoint but does not state a numerical group contrast or the statistical model used to estimate it.

Why does the randomized comparison matter?

In general, randomization is intended to make treatment groups comparable at the start of a trial, reducing systematic differences in assignment. A placebo-controlled comparison can help distinguish changes occurring during the study from changes that might also occur without the active treatment. These advantages depend on implementation, follow-up, outcome measurement, and analysis. Details of the randomization procedure, concealment, baseline balance, and endpoint analysis are not reported in the registry record, so those aspects cannot be assessed from the registry entries.

Blinding means that treatment assignment is concealed from specified participants or study personnel during the relevant phase. The registry identifies the study as double-blind. Blinding can, in general, limit the influence of expectations on care, reporting, or assessment. The record does not state which individuals were blinded or describe how blinding was maintained. The placebo group was offered open-label treatment after unblinding at the Posttreatment Week 4 visit, so that later phase differs from the blinded comparison.

How should uncertainty be read?

A confidence interval is a statistical range that expresses uncertainty around an estimate under a specified method. Its width is influenced by the amount of information and the variability in the data, among other factors. A narrow interval generally indicates more precise estimation than a wide interval, while the interval’s location indicates which values are compatible with the analysis. General interpretation also requires attention to the chosen confidence level and model assumptions. No interval for the primary endpoint is reported in the registry record.

A p-value, in general, describes how incompatible observed data are with a specified null hypothesis under the model assumptions; it is not the probability that the null hypothesis is true and does not measure clinical importance. The registry entries do not report a primary endpoint p-value or identify a statistical test. It is therefore not possible to characterize statistical evidence for the primary comparison. The absence of a reported p-value is not equivalent to a non-significant result.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variability is greater than a statistical model expects. If a model assumes less variability than the data contain, uncertainty can be understated and statistical evidence can appear stronger than warranted. The relevance of this issue depends on the outcome and model. The primary endpoint is continuous and is described using a mean and standard deviation; no model or over-dispersion assessment is reported in the registry record. This general concept should not be taken as a description of an issue observed in this trial.

What are the sample-size illustrations for?

The planning illustrations are described as calculations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They consider the effect to detect as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not a record of the trial’s original design justification. Their equal-allocation assumption differs from the study’s 2:1 blinded-phase allocation. The values of the illustrations and the trial’s own sample-size justification are not reported in the registry record.

In general, sample-size planning depends on assumptions about the effect considered important, variability, type I error, desired power, allocation, and the analysis method. A calculation based on an effect observed in the same trial is retrospective and can be sensitive to that estimate. It does not establish the probability that the trial has detected an effect, nor does it replace the effect estimate and its uncertainty. No additional calculation is made from the registry information.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures and 14 analyses. The outcomes span cerebral metabolism, SVR at multiple follow-up times, several neurocognitive domains, and physical and mental health-related quality-of-life scores. When many outcomes or time points are examined, the chance of at least one apparently notable result can increase if each is tested separately. In general, a prespecified hierarchy or multiplicity adjustment can help control the interpretation of a family of tests. The statistical plan and any multiplicity adjustment are not reported in the registry record.

The primary outcome is identified as change from baseline in the NAA + NAAG MRS ratio at Posttreatment Week 4. However, the registry notes that the primary outcome has several categories or time points and is not reduced to one comparison. The registry entries do not specify how the three brain areas were combined or analyzed, whether there was a separate estimate for each area, or which contrast was intended as the principal inferential comparison. These details are not reported in the registry record.

Missing-data handling is also not reported in the registry record. There is no information about missing endpoint measurements, reasons for missingness, imputation, or sensitivity analyses. Missing data can affect interpretation if participants with observed measurements differ systematically from those without them. The direction and size of any such effect cannot be inferred without the data and analysis details.

The named Full Analysis Set consists of participants randomized and given at least 1 dose. The record does not report the number analyzed for the primary endpoint, deviations from the analysis population, or whether other populations were used for particular outcomes. These omissions limit assessment of the analysis population and its relationship to the randomized groups.

11. 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 non-serious adverse event terms

The serious adverse-event figures list 0 participants affected among 26 at risk in the LDV/SOF blinded phase, and 0 among 14 at risk in the placebo blinded phase. In the open-label phase following placebo, the record lists 0 affected among 14 at risk. These are counts of participants affected, not a complete description of event type, timing, severity, or exposure duration. They should be read as the posted serious adverse-event counts for the listed groups, not as proof that no safety events of any kind occurred.

The record also lists other adverse events affecting 20 of 26 participants in the LDV/SOF blinded phase, 12 of 14 in the placebo blinded phase, and 9 of 14 in the open-label phase. These counts are distinct from the serious adverse-event counts. The record does not include serious adverse-event terms in the list of leading serious terms; detailed event descriptions are not reported in the registry record. Death counts are not reported in the registry record.

The open-label group consists of participants initially assigned to placebo who were then offered LDV/SOF. Its safety count belongs to a different treatment phase and history from the blinded groups. The figures alone do not support a causal comparison of safety between phases or a broader judgment about safety.

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

The registry record documents a randomized, double-blind, placebo-controlled study designed to examine cerebral metabolism and neurocognition in treatment-naive and treatment-experienced adults with chronic genotype 1 HCV infection. It identifies change in the NAA + NAAG MRS metabolic ratio at 4 weeks after treatment discontinuation as the primary outcome and describes measurement in three brain regions. These registry entries establish what the study intended to measure; they do not establish what the measured result was.

The numerical primary endpoint findings, including group-specific estimates and uncertainty, are not reported in the registry record. Therefore, the registry entries do not show the magnitude or direction of change, the precision of an estimate, or whether the randomized groups differed. They also do not permit a judgment about how any observed measurement change relates to neurocognition or to a clinically meaningful outcome. Such judgments require results and context that are not available in the record.

The study also listed SVR, neurocognitive function, and health-related quality of life outcomes. The presence of those endpoints in the registry is not evidence of a particular result. Their numerical findings are not reported in the registry record. Likewise, the safety counts describe participants affected in the listed phases, but do not provide enough detail to characterize event types or compare safety causally across phases.

In general, a study’s design can support a particular kind of inference, but the design cannot substitute for outcome data. Randomization and blinding are relevant to a treatment-group comparison during the blinded phase; the later open-label period has a different comparison structure. The results, analysis methods, missing-data handling, and multiplicity approach would be needed to assess the strength and scope of evidence. The information in the registry record supports describing the study’s aims, design, endpoint definition, and posted safety counts, but not making a claim that treatment did or did not alter cerebral metabolism or neurocognition.

13. Why This Trial Matters Statistically

This trial is statistically notable for linking a biological measurement with neurocognitive outcomes in a randomized, blinded design. The primary endpoint uses MRS to measure an NAA + NAAG signal relative to creatine in three specified brain areas. That ratio is a continuous measure, so interpretation depends on the estimated change, variability, and uncertainty—not merely on whether a measure was collected.

The blinded phase was planned with a 2:1 allocation, while the planning illustrations described in the record assume equal allocation. This distinction matters because sample-size illustrations depend on their assumptions and should not be treated as a description of the trial’s actual allocation or as observed power. The original sample-size justification is not reported in the registry record.

The study also illustrates the importance of defining the inferential target when an outcome spans multiple brain regions and when a trial has many outcome measures and analyses. The record lists a primary endpoint, but does not reduce its several categories or time points to one comparison in the available information. Without the statistical plan, analysis details, and numerical estimates, readers cannot determine how the endpoint’s components were handled or how multiplicity was addressed.

Finally, the change from a blinded placebo-controlled phase to an open-label treatment offer changes the context for interpreting later observations. Separating randomized comparisons from later treatment experience is essential to avoid treating unlike phases as though they were equivalent. The record makes those design stages visible, while leaving the primary endpoint results and important analytical details unreported.

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 main limitation for statistical interpretation is that numerical results for the primary endpoint are not reported in the registry record. There are no posted group means, standard deviations, changes, confidence intervals, or primary comparison estimates in the registry record for this analysis. The result’s direction, magnitude, and precision therefore cannot be assessed.

The endpoint is described across the basal ganglia, frontal cortex, and dorsolateral prefrontal cortex, but the record does not specify how measurements from these areas were combined or whether separate comparisons were made. It also does not provide the analysis model, the exact contrast, or the handling of multiple outcome measures and time points. These details are important for understanding which statistical question was answered.

The registry lists 40 participants enrolled, but the number included in each endpoint analysis and the number with missing measurements are not reported. Missing-data methods, sensitivity analyses, and analysis-population deviations are not reported in the registry record. Baseline characteristics and randomization implementation are also not described in the registry record for this analysis.

The study was single-center, and enrollment was 40. Those design details define the context but do not establish how representative the participants were or how precise the estimates would have been. The registry record does not provide the study’s original sample-size justification. The later open-label phase followed unblinding and placebo exposure, so it does not have the same comparison structure as the blinded randomized phase. Finally, detailed serious adverse-event terms and death counts are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ledipasvir/Sofosbuvir Fixed-Dose Combination on Cerebral Metabolism and Neurocognition in Treatment-Naive and Treatment-Experienced Participants With Chronic Genotype 1 HCV Infection — NCT02219685.
• Registry record last updated 2018-11-16; status last verified 2016-10.
• Results first posted 2016-11-30.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT02219685 was a completed Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel-group study with enrollment of 40. It examined LDV/SOF FDC in treatment-naive and treatment-experienced adults with chronic genotype 1 HCV infection. During the blinded phase, participants were assigned in a 2:1 allocation to LDV/SOF or placebo for 12 weeks. After unblinding at Posttreatment Week 4, the placebo group was offered open-label LDV/SOF for 12 weeks.

The primary outcome was change from baseline in the NAA + NAAG MRS metabolic ratio 4 weeks after therapy discontinuation. The registry also lists SVR, neurocognitive, and health-related quality-of-life outcomes. The primary endpoint’s numerical results and key analysis details are not reported in the registry record. Serious adverse-event counts were 0 in each listed phase; other adverse events were recorded in all three groups.