Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Velpatasvir in Participants With Chronic HCV Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Velpatasvir in Participants With Chronic HCV Infection (NCT01740791), a randomized phase 1 study. The primary outcome is Percentage of Participants Experiencing Treatment Emergent Adverse Events.

2. Clinical Question

3. Trial Design

This completed Phase 1b study was randomized, quadruple-masked, and used a parallel-group model. Its official title describes a multiple-dose ranging study of GS-5816, now named velpatasvir, in people with chronic hepatitis C virus infection. The record reports enrollment of 103 participants. Study start was 2012-11-06, and primary completion was 2013-03-15.

Participants were assigned to placebo or to a velpatasvir dose group. Arm descriptions specify a once-daily regimen for 3 days under fasted conditions. Dose groups were organized by HCV genotype: genotype 1a groups included 5 mg, 25 mg, 50 mg, 100 mg, and 150 mg; genotype 1b and genotype 2 groups included 150 mg; genotype 3 groups included 25 mg, 50 mg, and 150 mg; and genotype 4 included 150 mg. A further genotype 2 group received velpatasvir up to 400 mg. The posted primary endpoint results, however, list dose-level arms rather than separate genotype-specific results.

The primary objective was to evaluate safety, tolerability, and antiviral activity in treatment-naive participants with genotypes 1-6. The primary posted outcome was the percentage experiencing treatment-emergent adverse events. Listed secondary outcomes include HCV RNA measures and pharmacokinetic parameters. The registry record reports 13 outcome measures, 10 posted secondary outcomes, and no posted analyses. The original study's sample-size justification, detailed statistical analysis plan, and rationale for the specific dose groups are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: 163 participants were screened. Participants were not enrolled in 'Velpatasvir up to 400 mg genotype (GT) 2' group.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug (velpatasvir or placebo). Data were summarized by velpatasvir or placebo.

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: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug (velpatasvir or placebo).

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Experiencing Treatment Emergent Adverse Events, measured over First dose date up to Day 17 + 2 (Day 19 if Day 17 visit missing).

The primary endpoint is the percentage of participants experiencing a treatment-emergent adverse event. An event qualified if it was new or worsening and began on or after the date of the first study-drug dose, within the endpoint's follow-up window. That window ran from the first dose through the Day 17 study visit date plus 2 days, or Day 19 if the Day 17 visit was missing.

The endpoint uses the safety analysis set: participants who were randomized and received at least 1 dose of velpatasvir or placebo. Results were summarized by velpatasvir or placebo. The posted arm results give both the number of participants at risk and the percentage with an event. This binary endpoint treats each participant as having experienced at least one qualifying event or not; it does not describe the number, duration, severity, or timing of all events per participant.

In general, a treatment-emergent event endpoint is used to describe adverse events occurring during a defined exposure and observation period. It offers a straightforward comparison of the proportion of participants with events across groups. It is not, by itself, a complete account of safety: interpretation also depends on event severity, seriousness, type, follow-up, and the amount of information available. The registry record does not report a separate severity breakdown for this primary endpoint.

7. Results Posted in the Registry

• Velpatasvir 25 mg: 26.7% (4/15) versus 17.6% (3/17) on control; risk difference 9.0 percentage points (95% CI -19.8 to 37.8), risk ratio 1.51 (0.40–5.69); unadjusted two-proportion z-test p = 0.538.
• Velpatasvir 50 mg: 8.3% (1/12) versus 17.6% (3/17) on control; risk difference -9.3 percentage points (95% CI -33.2 to 14.6), risk ratio 0.47 (0.06–4.01); unadjusted two-proportion z-test p = 0.474.
• Velpatasvir 150 mg: 29.0% (9/31) versus 17.6% (3/17) on control; risk difference 11.4 percentage points (95% CI -12.8 to 35.5), risk ratio 1.65 (0.51–5.27); unadjusted two-proportion z-test p = 0.384.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either met the definition of having at least one treatment-emergent adverse event during the endpoint window or did not. The percentage is therefore a proportion, with the safety analysis set as its denominator. In general, proportions are useful for outcomes where participants are classified into event and no-event categories, but the estimate can be imprecise when the denominator is small. That is relevant to these results because arm sizes range from 4 to 31 participants.

What do the arm percentages describe?

The arm percentages are descriptive summaries for placebo and each posted velpatasvir dose. The underlying counts are 3 events among 17 placebo participants; 1 among 4 at 5 mg; 4 among 15 at 25 mg; 1 among 12 at 50 mg; 3 among 8 at 100 mg; and 9 among 31 at 150 mg. They describe the percentage of participants with one or more qualifying events, not the total number of individual events. A participant with multiple events remains a participant with an event for this endpoint.

The denominator is defined by the registry's safety analysis set, which includes randomized participants who received at least 1 dose. The primary endpoint period begins on the first-dose date and ends at the specified Day 17 visit date plus 2 days, with Day 19 used when the Day 17 visit is missing. In general, a clearly defined risk window is important because event percentages depend on the period during which events are collected. The registry record does not report how events after that window were handled in any other analyses.

How should the unadjusted comparisons be read?

The comparison estimates are described as recalculated, simple unadjusted comparisons based on the posted summary statistics. They compare the proportion with an event in a selected velpatasvir dose group with the proportion in the placebo group. A risk difference is a difference between two event proportions; a value above zero indicates a higher observed proportion in the velpatasvir group, while a value below zero indicates a lower observed proportion in that group. This direction describes the estimate and does not establish a causal effect.

The posted intervals accompany those risk-difference estimates. In general, an interval conveys the range of values reasonably compatible with the data under the method used; a wider interval indicates less precision. The confidence level and interval-construction method are not reported in the registry record, so they should not be inferred from the displayed limits. The unadjusted p-values are 0.538 for 25 mg, 0.474 for 50 mg, and 0.384 for 150 mg. In general, a p-value measures how unusual the observed data would be under a specified null hypothesis and model; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. These values do not replace consideration of the estimates and their intervals.

The listed risk ratios and odds ratios are additional relative-effect summaries, but they are also based on small event counts. In general, relative measures compare proportions or odds on a ratio scale, whereas a risk difference expresses an absolute contrast. Ratios can look large or small while the absolute difference remains uncertain. These measures are unadjusted, and their uncertainty is substantial in the posted results. No adjusted model estimates are reported.

Why can sparse data limit inference?

When few participants experience an event, a change in the classification of even one participant can noticeably alter an arm's proportion. Small denominators also tend to yield broad uncertainty intervals. In general, sparse binary data can make conventional approximations less dependable, depending on the analysis method. The registry record does not report the method used to construct the recalculated intervals or p-values, and no alternative exact analysis is posted. It is therefore appropriate to treat the calculations as exploratory descriptions rather than as a replacement for a prespecified trial analysis.

The design includes multiple dose levels and genotype-specific regimens. In general, evaluating several groups creates multiple opportunities to observe apparently different results by chance. A multiplicity strategy can define how such comparisons are controlled or interpreted. No such strategy is reported in the registry record. In addition, the posted comparisons omit some dose arms, including the 5 mg and 100 mg groups, and they do not give separate comparisons by genotype. The reason for the selected comparisons is not reported.

The trial's own statistical methods, including the original sample-size justification, planned model, missing-data procedures, and any interim analyses, are not reported in the registry record. Those omissions matter when evaluating whether a comparison was planned, which participants were included in each analysis, and how much weight to place on exploratory calculations. The posted safety set definition is available for the primary endpoint, but a corresponding analysis-population definition for secondary antiviral and pharmacokinetic outcomes is not reported.

10. Confidence Intervals and Precision

Precision concerns how much uncertainty surrounds an estimate. The primary arm percentages are based on small groups, ranging from 4 to 31 participants, so each percentage is a limited summary of the observed participants rather than a highly stable estimate of an underlying event rate. The registry does not post uncertainty intervals for those individual arm percentages.

For the three recalculated risk differences, the intervals are wide and cross zero: 0.090 with limits -0.198 and 0.378 for 25 mg; -0.093 with limits -0.333 and 0.146 for 50 mg; and 0.114 with limits -0.128 and 0.355 for 150 mg. In general, an interval crossing zero for a difference indicates that the data are compatible with values on both sides of no difference, under the interval method used. The displayed intervals also permit potentially meaningful differences in either direction, so the estimates do not pin down a precise contrast.

The confidence level and method for these intervals are not reported in the registry record. The observed group percentages and intervals should therefore be interpreted with the available sample sizes and the unadjusted nature of the calculations in mind. The interval width does not show that groups are equivalent; rather, it reflects that the comparison is not precise enough to rule out a range of possible differences. Likewise, a p-value alone does not indicate how precise an estimate is or whether a difference would be important.

In general, larger study groups and more events can improve precision, while low event counts and multiple subgroup comparisons can leave estimates unstable. Here, the combination of small arm sizes, sparse event counts, and genotype-specific dose arrangements limits how finely the primary safety results can be interpreted.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed risk differences, not the original trial's sample-size calculation. Each entry gives participants per arm for the stated power level; these are not total participants and are not event counts. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial's original sample-size justification and design assumptions are not reported in the registry record.

The 80% power column means the illustrated number of participants per arm for a design with an 80% chance of detecting the specified effect under the listed assumptions, if that effect and assumptions were correct. The 90% power column uses a higher target chance of detecting that effect, and consequently its participant requirement is larger. For example, for the 25 mg comparison, planning for 100% of the observed effect gives 332 participants per arm for 80% power and 444 participants per arm for 90% power. The corresponding figures for 75% of the observed effect are 569 and 761; for 50%, they are 1,230 and 1,646.

Smaller effects are harder to distinguish from random variation, so planning for a smaller fraction of the observed effect requires more participants. This is apparent across the listed comparisons. These projected numbers are not observed power, do not describe the number enrolled in the completed trial, and do not imply that the original study was designed around these contrasts. They are conditional planning illustrations and should be read alongside the uncertainty in the observed effects and the limitations of using small-study estimates as planning inputs.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.176; treatment proportion p₁ = 0.267; average p̄ = 0.222.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5873 = 1.1511.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5839 = 0.4914.
4. n = (1.1511 + 0.4914)² / (0.0902)² = 331.6, rounded up to 332 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.176470588235294                          # control proportion
p1 <- 0.266666666666667                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1740791)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 332 (80% power), 444 (90% power)
 75% of observed effect: n per arm = 569 (80% power), 761 (90% power)
 50% of observed effect: n per arm = 1,230 (80% power), 1,646 (90% power)
power.prop.test: 331.6 
Simulated power at n = 332 per arm: 0.797 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The study evaluated several dose groups, with regimens organized by HCV genotype, and the registry lists multiple secondary outcomes. The primary endpoint is the percentage experiencing treatment-emergent adverse events; the secondary outcomes include HCV RNA measures and velpatasvir pharmacokinetic parameters. When multiple outcomes, doses, or subgroup comparisons are examined, the chance of observing an unusual result by chance can increase. In general, a prespecified multiplicity strategy may control the overall error rate or distinguish confirmatory from exploratory comparisons. Such a strategy is not reported in the registry record.

The posted recalculated comparisons cover 25 mg, 50 mg, and 150 mg against placebo. The record does not explain why these dose comparisons were selected, whether they were planned in advance, or how comparisons involving the other dose arms were treated. The reported p-values are unadjusted. They should not be interpreted as accounting for the set of possible dose, genotype, and outcome comparisons.

The primary endpoint's analysis population is defined as randomized participants who received at least 1 dose of study drug. This identifies the safety analysis set for the posted primary outcome. The registry record does not report detailed missing-data methods, how missing endpoint observations were handled, whether any participants were excluded after randomization, or how missing secondary outcome data were treated. The endpoint definition gives a fallback date when the Day 17 visit is missing, but it does not describe a general missing-data strategy.

The registry record reports no posted analyses. A statistical analysis plan, model specifications, handling of protocol deviations, planned interim analyses, and the original sample-size justification are not reported in the registry record. It is also not reported whether the primary endpoint analysis was prespecified in the form represented by the posted summary. These gaps limit the ability to distinguish planned confirmatory analyses from exploratory summaries. The reported safety-set definition and endpoint window remain useful for understanding what the posted percentages represent, but they do not fill in the absent inferential plan.

14. 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 non-serious adverse event terms

The serious adverse event figures count participants with at least one serious adverse event in each group. The posted number at risk is 17 for placebo, 4 for velpatasvir 5 mg, 15 for 25 mg, 12 for 50 mg, 8 for 100 mg, and 31 for 150 mg. The number affected is 0 in every group. The record also reports 0 deaths in each group, and no top serious-event terms are listed.

These are counts, not evidence that serious events could not occur. With these group sizes, zero observed events means only that no serious adverse events were recorded in the listed groups over the reported observation period. It does not establish that the underlying risk is zero or rule out uncommon events. The registry record does not specify a separate follow-up window for these serious-event figures, so they should not automatically be assumed to have the same endpoint window as the primary treatment-emergent adverse-event outcome.

The figures address serious events only; they do not summarize non-serious adverse events, event severity overall, or the full clinical context. The primary endpoint percentages are a separate measure of treatment-emergent adverse events and include events that need not be serious.

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

The posted primary endpoint describes the proportion of participants in each dose group who experienced at least one treatment-emergent adverse event during the defined follow-up window. Percentages range from 8.3% in the 50 mg group to 37.5% in the 100 mg group, while the placebo percentage is 17.6%. The groups are small, the percentages vary, and the pattern is not a basis for inferring a dose relationship. The arm descriptions also correspond to distinct genotype settings, so the posted dose-level summaries do not isolate dose from all other group features.

The unadjusted recalculated contrasts for 25 mg, 50 mg, and 150 mg each have intervals spanning zero. This means that the observed data do not provide a precise estimate of the difference from placebo. The values do not establish that the groups are the same, and they do not show a reliable increase or decrease in event risk. No multiplicity adjustment or sponsor-reported inferential analysis is posted for these comparisons.

The serious-event summaries report no affected participants and no deaths in the listed arms. Those counts are informative descriptions of what was recorded in this trial, but the small groups cannot establish the absence of uncommon risks. The primary endpoint is also limited to a specified period beginning at first dose; it does not describe later events.

The study's stated objectives included safety, tolerability, and antiviral activity, and its listed secondary outcomes cover HCV RNA and pharmacokinetic measures. The primary endpoint results alone do not answer the antiviral or pharmacokinetic questions. The registry record does not report enough analysis detail to reconstruct the original testing strategy, missing-data handling, or sample-size rationale. Accordingly, the results support a narrow reading of observed short-term event proportions and their uncertainty, not a broad conclusion about treatment effects or safety beyond the studied groups and reported period.

16. Why This Trial Matters Statistically

This trial illustrates several statistical issues that arise in early, dose-ranging studies. Dose groups can be small, and a binary safety outcome may include only a few events in each arm. In that setting, percentages can vary substantially from one group to another, while estimates comparing groups remain imprecise. Displaying the counts alongside the percentages helps readers see the amount of information underlying each summary.

The study also combines dose-ranging with genotype-specific regimens. This makes a simple dose-by-dose comparison harder to interpret because the arm descriptions do not represent one uniform population across all doses. The primary endpoint results are posted by dose rather than by genotype, and the record does not report genotype-specific estimates for that endpoint. A statistical interpretation should therefore avoid treating the pattern as a clean dose-response analysis.

The recalculated risk differences and their intervals show why point estimates and uncertainty should be considered together. The estimates point in different directions across the selected comparisons, but each interval allows a broad range of possible contrasts. Unadjusted p-values alone would not convey that range. Multiple dose groups and secondary outcomes also raise questions about multiplicity and which analyses were prespecified; the registry record does not provide those details.

Finally, the planning illustrations demonstrate that projected sample sizes depend on the effect size chosen and the assumptions used. They are separate from the trial's original design, which is not documented in the registry record. Keeping that distinction clear prevents a retrospective planning calculation from being mistaken for the study's intended power or design target.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary endpoint is limited to treatment-emergent adverse events in the safety analysis set and to a defined period after the first dose. The registry record does not report event-specific severity results for this endpoint, nor does it provide the full clinical context or timing of each event. The serious-event counts have no affected participants in any listed arm, but the small group sizes limit what those zeros can establish.

Arm sizes are small and vary across the posted dose groups. Some groups have only 4 or 8 participants. Percentages from such groups are sensitive to individual event classifications, and the recalculated comparisons have wide intervals. The posted arm summaries are not separated by genotype, despite dose groups being described in genotype-specific terms. The reasons for this aggregation and the composition of each dose-level safety group are not reported in the registry record.

Only three unadjusted dose comparisons are posted. The record does not explain their selection, report adjusted analyses, or describe a multiplicity plan. Nor does it report the method used for the recalculated intervals and p-values, the trial's own statistical analysis plan, or its original sample-size justification. Missing-data procedures and the analysis populations for secondary outcomes are not reported in the registry record.

The study's stated objective includes antiviral activity, and secondary outcomes include HCV RNA and pharmacokinetic measures, but those results are not included in the primary safety summaries. The described dosing period was 3 days; the registry record does not establish longer-term safety from this primary endpoint. The available results therefore have limited scope and precision.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Velpatasvir in Participants With Chronic HCV Infection — NCT01740791.
• Registry record last updated 2020-12-16; status last verified 2020-12.
• Results first posted 2020-12-16.
• 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.

21. Record Summary

This completed, randomized, quadruple-masked, parallel-group Phase 1b study enrolled 103 participants with chronic HCV infection. The described velpatasvir regimens were once daily for 3 days under fasted conditions, with placebo as control. The primary endpoint was the percentage experiencing a treatment-emergent adverse event in the safety analysis set during the specified post-dose window.

Posted event percentages range from 8.3% to 37.5% across the velpatasvir dose groups, compared with 17.6% for placebo. The three recalculated unadjusted risk-difference intervals span zero. No serious adverse events or deaths are listed in any group. The small groups, genotype-specific dose structure, unadjusted comparisons, and limited reported analysis details constrain interpretation. The registry record does not report the original sample-size justification, multiplicity strategy, or missing-data methods.