Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 or 24 Weeks in Genotype 1 or 4 HCV Infected Adults With Sickle Cell Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 or 24 Weeks in Genotype 1 or 4 HCV Infected Adults With Sickle Cell Disease (NCT02301936), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12).

2. Clinical Question

The study’s stated objectives were to evaluate antiviral efficacy, safety, and tolerability of LDV/SOF in this population. Secondary outcomes included SVR4, HCV RNA measurements during treatment and change from baseline, virologic failure, and changes in health-related quality of life and fatigue scores. These outcomes describe different aspects of viral response and participant experience; they do not replace the prespecified primary endpoint.

The central statistical issue is not simply whether the observed response percentage would be high or low. The registry record does not give the primary response count or percentage, and the study enrolled a small group. Without the primary result and its uncertainty, the magnitude and precision of the estimated response cannot be assessed. The non-randomized allocation also means that any contrast between durations would be difficult to separate from differences in the participants assigned to each group.

3. Trial Design

This was a phase 2, open-label, parallel-group study with non-randomized allocation. The registry record gives planned enrollment as 10 and status as completed. The recorded study start was 2015-03-02, and primary completion was 2016-04-18. The sponsor was Gilead Sciences. These administrative details describe the registered study, but do not provide information about the conduct of individual visits or the analysis process.

Two LDV/SOF durations were described. Treatment-naive or treatment-experienced participants without cirrhosis were assigned to the 12-week description. Treatment-experienced participants with cirrhosis were assigned to the 24-week description. Since allocation was not randomized and participant characteristics were used to describe the groups, duration was not the only apparent distinction between them. A direct difference in outcomes between these groups would therefore not isolate the effect of duration.

Open-label means masking was not used, as indicated in the registry record. This can matter for outcomes influenced by knowledge of treatment, including self-reported health-related quality-of-life and fatigue measures. The primary endpoint is based on a laboratory measure, but open-label status still describes the study design as a whole. The record does not report further procedures intended to limit bias in outcome measurement.

The study was parallel rather than crossover: the record describes distinct groups receiving different durations, not participants switching between durations. The record does not report a randomized allocation sequence, a comparator receiving a different intervention, or a placebo group. Accordingly, the study is best read as an evaluation of outcomes in participants receiving LDV/SOF under the stated group descriptions, rather than as a controlled estimate of the effect of one duration relative to another.

The enrollment figure is a planning and registration detail, not a substitute for the number contributing to each outcome. For safety outcomes, the registry lists 9 participants at risk in the 12-week group and 1 in the 24-week group. These group sizes are notably uneven, and precision for group-specific estimates would be limited, especially for the smaller group. The registry record does not report a sample-size justification or explain the basis for these group sizes.

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: Full Analysis Set: participants who took 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 took at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12), measured over Posttreatment Week 12.

The primary endpoint was the percentage of participants with sustained virologic response 12 weeks after discontinuing therapy. SVR12 was defined as HCV RNA below the lower limit of quantitation (LLOQ) at posttreatment week 12. The endpoint is a binary outcome at the participant level: each participant either meets the stated viral RNA criterion at the specified assessment or does not. The reported percentage would express the proportion meeting that criterion among the defined analysis population.

SVR12 is used in HCV studies as a measure of virologic response after treatment has ended. Assessing the outcome after discontinuation distinguishes it from an on-treatment HCV RNA measurement, which records viral RNA status while study drug is being taken. The posttreatment timing is part of the endpoint definition and must be retained when interpreting any response percentage.

The registry record defines the primary analysis population as the Full Analysis Set: participants who took at least 1 dose of study drug. It also identifies posttreatment week 12 as the timeframe. However, it does not report the number in this population who met the endpoint, the denominator used for the percentage, or the resulting percentage. It also does not report an uncertainty interval for the endpoint. Thus, the endpoint is clearly defined, but its estimated value and precision are not available in the registry record.

A confidence interval, in general, describes a range of values compatible with the data under the assumptions of the statistical method. For a response percentage, it would help communicate how much uncertainty remains around the estimate, particularly when the study group is small. No such interval for SVR12 is reported in the registry record. Without the result and its uncertainty, the endpoint definition alone does not establish what response was observed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods for a clinical trial need to connect the question, outcome definition, analysis population, and comparison being made. In this study, the question concerned the percentage of participants meeting a binary virologic criterion at a specified posttreatment time. The registry record reports this endpoint definition, but does not report the statistical analysis methods or the primary result. The concepts below are general explanations, not claims about methods used in this study.

What does a percentage estimate?

For a binary endpoint, a response percentage is calculated from the number of participants meeting the endpoint and the number included in the analysis denominator. The resulting estimate describes the observed fraction in that analysis population. It does not by itself show the precision of the estimate, establish a treatment effect, or explain why a participant did or did not meet the criterion. The record identifies the Full Analysis Set as participants who took at least 1 dose, but does not report the endpoint numerator or denominator.

When a study group is small, each participant’s outcome can have a substantial influence on the reported percentage. This makes uncertainty intervals particularly useful. A confidence interval is a statistical range intended to show uncertainty around an estimate under specified assumptions and a chosen method. Different interval methods can behave differently for small samples or proportions near the boundaries. The registry record does not name an interval method or report a confidence interval for SVR12, so neither can be attributed to this trial.

Why does allocation matter?

Random allocation is a design method intended to make treatment groups comparable, on average, with respect to measured and unmeasured characteristics. Here, allocation is recorded as non-randomized. The group descriptions also differ by treatment history and cirrhosis status. Consequently, an unadjusted comparison of group percentages would mix the duration contrast with differences in who was placed in each group. Statistical adjustment can address measured characteristics under appropriate assumptions, but it cannot guarantee removal of confounding from unmeasured or poorly measured factors. The registry record does not report an adjusted comparison or a statistical plan for such an analysis.

The groups also have very different recorded numbers at risk for safety outcomes: 9 in the 12-week group and 1 in the 24-week group. Unequal group sizes affect the precision of group-specific estimates and make a small group especially vulnerable to instability. A count of no events in a small group should not be read as proof that the underlying event risk is absent. It is a description of what was recorded among the participants at risk.

How should a binary primary outcome be analysed?

In general, the analysis should define the outcome and assessment time before examining results, specify the analysis population, and explain how missing outcome measurements are handled. It should also make clear whether the target is a response percentage within a group or a contrast between groups. For an estimate within a group, the key quantities are the number meeting the criterion and the denominator. For a comparison, the design and assumptions supporting the contrast must also be stated.

The endpoint is measured at posttreatment week 12 and is defined using HCV RNA relative to the LLOQ. This definition identifies the outcome threshold and timing, but it does not say how an unmeasured posttreatment result was handled, whether repeat or confirmatory assessments were used, or whether any sensitivity analyses were conducted. Those details are not reported in the registry record. They should not be inferred from the endpoint label.

Multiplicity is another general concern when a study evaluates multiple outcomes. Testing or interpreting many outcomes can increase the chance of emphasizing a result that appears notable by chance. A statistical plan may identify one primary endpoint and describe how secondary outcomes are to be interpreted or adjusted. The record identifies one primary outcome and lists secondary outcomes, but does not report a multiplicity strategy. The absence of a reported strategy does not establish that none was used; it means the registry record does not document one.

What can planning calculations tell a reader?

Sample-size calculations are planning exercises based on assumptions about the anticipated effect, variability or event frequency, statistical threshold, allocation, and analysis method. They are not observed outcomes and do not tell whether a result from the completed study is statistically significant. The registry record does not report a sample-size justification. Any illustrative calculation based on an observed effect should be understood as a planning illustration, not as observed power or as evidence that the original trial was designed to detect that effect.

Power is a property of a planned design under specified assumptions, not a retrospective measure of whether a completed result is credible. After a study is complete, the estimate and its uncertainty are more informative than a post hoc statement about power. The record does not report the assumptions used to justify enrollment. It also does not report the observed SVR12 estimate needed to anchor an illustration based on an observed effect.

For a binary outcome, a planning calculation needs an assumed response pattern and a definition of the comparison of interest. In this study, a direct comparison between treatment durations would also require caution because allocation was non-randomized and participant profiles differ by group. A calculation that assumes equal allocation or a specified effect does not make the actual group assignment randomized, nor does it remove confounding. The assumptions attached to any planning illustration should therefore be kept separate from the trial’s actual design and findings.

Why are analysis populations important?

An analysis population specifies which participants contribute to a particular estimate. The record defines the Full Analysis Set as participants who took at least 1 dose. That definition helps identify the intended population for the primary outcome, but does not indicate how many participants had an evaluable posttreatment measurement. It also does not state whether participants with missing measurements were counted as nonresponders, omitted from the denominator, or handled another way. These choices can affect the reported response percentage.

In general, a complete analysis report should make the denominator transparent, explain missing-data rules, describe any departures from the planned analysis, and present the estimate with an appropriate measure of uncertainty. The registry record does not report these details for SVR12. It lists zero analyses in the posted record, but that entry does not explain what analyses may have been conducted outside the registry or whether a full results report exists elsewhere. No such information should be assumed from the registry entry alone.

Finally, adverse event summaries use a different kind of denominator from the primary efficacy endpoint. The safety entries specify participants at risk and participants affected for serious and other adverse events. Those counts describe safety reporting in the listed groups; they do not provide the SVR12 analysis denominator. Separate outcomes require separate definitions and denominators, and one should not be substituted for the other.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("LDV/SOF 12 Weeks", "LDV/SOF 24 Weeks")
n      <- c(9, 1)
events <- c(8, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  LDV/SOF 12 Weeks  9  8  88.9  51.8  99.7  56.5  98.0  55.5  97.5
ARM  LDV/SOF 24 Weeks  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies SVR12 as the primary outcome and lists secondary outcomes that include SVR4, on-treatment HCV RNA below the LLOQ, change in HCV RNA from baseline, virologic failure, and changes in physical and mental health-related quality of life and fatigue. It does not report a multiplicity strategy describing how inferences across these outcomes were to be controlled or prioritized. Without that information, secondary findings would generally be interpreted as exploratory unless a fuller analysis plan establishes otherwise.

The record does not report the number of participants with an observed SVR12 measurement, the result denominator, or how missing posttreatment measurements were handled. The Full Analysis Set is defined as participants who took at least 1 dose, but that definition alone does not determine the rule for missing endpoint data. In general, treating missing results as failures, excluding them, or using another approach can lead to different estimates. No approach can be attributed to this study from the registry record.

The record also does not report an analysis plan, interim analyses, a sample-size justification, or adjustments for participant characteristics. These are not details that can be inferred from the study phase or enrollment. The posted registry information therefore permits a description of the intended endpoint and the stated analysis population, but not a full assessment of the analysis choices, missing-data assumptions, or multiplicity control.

The record lists zero analyses. This means no analysis entries are reported there; it does not establish whether analyses were performed elsewhere. Likewise, a missing analysis description should be reported as not reported in the registry record rather than interpreted as proof that a particular method was not used.

12. 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: sickle cell anaemia with crisis (11.1%).

The safety entries give group-specific counts of participants at risk and participants affected. For serious adverse events, 9 participants were at risk in the 12-week group and 1 was affected; 1 participant was at risk in the 24-week group and 0 were affected. For other adverse events, 9 were at risk and 6 were affected in the 12-week group, while 1 was at risk and 1 was affected in the 24-week group. The recorded number of deaths was 0 in each group.

These are descriptive counts, not evidence that one duration is safer than the other. Allocation was non-randomized, the group descriptions differ, and the numbers at risk are uneven. In general, small denominators make event percentages unstable, and an absence of recorded events in a small group does not establish that the event could not occur. Comparisons also require consistent definitions, follow-up, and exposure time, details not fully reported in the registry record.

The registry lists sickle cell anaemia with crisis as a serious adverse event term at 11.1%. The entry does not specify the group for that percentage, so it should not be assigned to either duration. The counts and event term also do not establish causation; the registry record does not report whether the event was considered related to study drug.

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

The registry record describes a phase 2 study evaluating LDV/SOF in adults with genotype 1 or 4 HCV infection and SCD. It specifies two treatment durations, the participant characteristics associated with each duration, and SVR12 as the primary endpoint. This information clarifies what the investigators intended to evaluate. It does not provide the numerical SVR12 result, so it cannot establish the proportion of participants who met the primary endpoint.

The absence of a posted primary result also prevents assessment of its precision. A response percentage is most informative when accompanied by its denominator and an uncertainty interval. Neither is reported for SVR12. The planned enrollment of 10 indicates the intended scale of the study, but does not substitute for the outcome data or show how many participants contributed to the endpoint analysis.

The two duration groups do not form a randomized comparison. Their registry descriptions distinguish participants by treatment history and cirrhosis status, and group allocation was non-randomized. Any observed difference between those groups would not, by itself, show that duration caused the difference. The record does not report an adjusted comparison that might account for measured participant differences, and such adjustment would still depend on assumptions.

The safety entries offer limited descriptive information: serious and other adverse event counts, participants at risk, and deaths. The uneven group sizes and non-randomized allocation limit comparative interpretation. The listed serious event term does not establish a causal relationship with treatment. These safety data should be understood as counts in the registry record, not as a complete characterization of risk.

In general, a completed trial can contribute useful evidence even when its registry record is incomplete, but conclusions must match the information actually reported. In this case, the record supports a description of the study question, design, outcome definitions, and selected safety counts. It does not support a conclusion about the primary response rate, comparative effectiveness of the two durations, or a causal treatment effect.

14. Why This Trial Matters Statistically

This study raises statistical issues that are important when interpreting clinical research in a narrowly defined population. The registry record concerns adults with HCV infection and SCD, and the planned enrollment was 10. A study of this scale can describe participant outcomes, but estimates are likely to have limited precision, and a small number of events can strongly influence group summaries. For that reason, counts, denominators, and uncertainty intervals matter alongside percentages.

The study also illustrates why duration groups should not automatically be treated as comparative arms. The record describes different participant profiles for the 12-week and 24-week groups and states that allocation was non-randomized. An observed difference could arise from the characteristics that distinguish the groups rather than from the duration itself. The design details are essential to interpreting any apparent contrast.

Outcome definition and outcome reporting are separate matters. The primary endpoint is clearly described as HCV RNA below the LLOQ at posttreatment week 12, but the record does not report the response result. A well-defined endpoint enables consistent interpretation when data are available; it does not replace those data. This distinction helps prevent a description of the study objective from being mistaken for a result.

The registry entry also shows why safety summaries require attention to denominators and event attribution. Serious and other adverse events are presented as counts among participants at risk, while the listed serious event term is not linked to a group in the record. Without a clear denominator and attribution, readers should avoid extending a reported event entry into a comparative or causal claim.

More broadly, transparent reporting of analysis populations, missing-data handling, multiplicity, and precision enables readers to evaluate how robust an estimate may be. These details are not reported in the registry record for the primary result. Identifying what is documented and what remains unreported is a central part of sound statistical interpretation.

15. 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 interpreting efficacy is that the registry record does not report the primary SVR12 result. It gives neither the number of participants meeting the endpoint nor the percentage, denominator, or confidence interval. As a result, the central outcome cannot be evaluated numerically from this record. The endpoint definition and timeframe alone do not reveal the observed response.

The planned enrollment was 10, and the safety entries show substantially uneven numbers at risk across the treatment groups: 9 in the 12-week group and 1 in the 24-week group. Small group sizes limit the precision of estimates and make direct contrasts unstable. The group assignment was non-randomized, and group descriptions differ by treatment history and cirrhosis status. These features limit causal interpretation of any group difference.

The record does not report the sample-size justification, analysis plan, missing-data rules, interim analyses, or multiplicity strategy. It does not state how many participants had evaluable SVR12 results or how missing posttreatment measurements were handled. Those omissions prevent a full evaluation of the statistical analysis and potential sensitivity of the primary estimate to analysis choices.

Safety reporting is also limited in scope. Counts are available for serious and other adverse events and deaths, and one serious event term is listed with a percentage. The record does not assign that percentage to a treatment group or establish whether the event was related to study drug. The available counts are therefore not a complete basis for comparing safety between durations.

These limitations concern what can be concluded from the registry record; they do not establish that unreported analyses or additional results do not exist elsewhere. Any further efficacy or safety assessment would require the relevant results and methodological details.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 or 24 Weeks in Genotype 1 or 4 HCV Infected Adults With Sickle Cell Disease — NCT02301936.
• Registry record last updated 2018-11-19; status last verified 2017-04.
• Results first posted 2017-05-25.
• 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.

19. Record Summary

NCT02301936 is a completed phase 2, open-label, parallel-group study sponsored by Gilead Sciences. It enrolled 10 adults with genotype 1 or 4 HCV infection and SCD, with a recorded start date of 2015-03-02 and primary completion date of 2016-04-18. Allocation was non-randomized.

The study evaluated LDV/SOF for 12 or 24 weeks. The registry describes the 12-week group as treatment-naive or treatment-experienced participants without cirrhosis, and the 24-week group as treatment-experienced participants with cirrhosis. The primary outcome was SVR12, defined as HCV RNA below the LLOQ at posttreatment week 12, in participants who took at least 1 dose.

The registry record does not report the primary outcome result or its precision. Safety counts are reported for serious and other adverse events and deaths. A sample-size justification, statistical analysis plan, and missing-data approach are not reported in the registry record.