Study to Evaluate Effect of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination on the Pharmacokinetics of a Representative Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Effect of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination on the Pharmacokinetics of a Representative Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol (NCT02533427), a na phase 1 study. The primary outcome is Pharmacokinetic (PK) Parameter: AUCtau of Norelgestromin.

2. Clinical Question

3. Trial Design

This was a Phase 1, open-label, drug-interaction study sponsored by Gilead Sciences. It was listed as completed. The registry gives a study start date of 2015-10-29 and a primary completion date of 2016-03-18. Enrollment was 15. Allocation is listed as not applicable, masking as none, and the model as single group. Those design features mean the record does not describe a randomized, blinded comparison between independently assigned treatment arms.

The study concerned SOF/VEL/VOX with VOX and norgestimate/ethinyl estradiol. Part A involved NGM/EE; the registry’s Part B group label identifies NGM/EE with SOF/VEL/VOX plus VOX. The brief summary states that participants without a documented history of taking NGM/EE for at least one menstrual cycle would receive NGM/EE, while participants with that history could enroll directly into Part B. The registry record’s detailed arm description is incomplete, so further sequencing, dosing, or visit details should not be inferred.

The primary endpoint was AUCtau of norelgestromin. The listed timeframe includes concentration measurements on Cycle 1, Study Day 14, and Cycle 2, Study Day 42, at predose and specified postdose times through 24 hours. The endpoint description defines AUCtau as the area under the concentration-versus-time curve over the dosing interval. The record also lists pharmacokinetic and safety secondary outcomes, including adverse events, laboratory abnormalities, and pharmacokinetic measures for contraceptive components and antiviral drugs.

The registry record does not report the sample-size justification, a detailed statistical analysis plan, or a randomized control comparison. The listed enrollment is not evidence by itself that the study was sized to estimate a particular effect with a specified precision.

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: 15 participants were screened.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The PK Analysis Set included all enrolled participants who took at least 1 dose of study drug and had at least 1 non-missing postdose plasma concentration value reported.

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 all enrolled participants who took at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter: AUCtau of Norelgestromin, measured over Cycle 1,Study Day 14: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; Cycle 2,Study Day 42: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose.

The primary endpoint, AUCtau of norelgestromin, represents the area under the drug concentration-versus-time curve over the dosing interval. It is a measure of total drug exposure during that interval, rather than a single concentration at a particular sampling time. In a pharmacokinetic interaction study, exposure measures can help describe whether the concentration profile of a drug changes in the presence of another drug or combination.

The registry lists the endpoint as a mean with standard deviation and specifies plasma concentration sampling on Cycle 1, Study Day 14, and Cycle 2, Study Day 42. Samples were scheduled predose and at multiple postdose times through 24 hours. The PK Analysis Set was defined as enrolled participants who took at least one dose of study drug and had at least one non-missing postdose plasma concentration value.

The endpoint is relevant to the stated drug-interaction question because it summarizes norelgestromin exposure across the dosing interval. However, the registry record does not report the observed mean, standard deviation, contrast between study periods or parts, or a confidence interval for AUCtau. Therefore, the endpoint definition and collection schedule can be described, but the magnitude and precision of the primary pharmacokinetic finding cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Pharmacokinetic analyses describe how drug concentrations change over time and summarize features of that concentration profile. AUCtau is the area under the concentration-versus-time curve over a dosing interval. It captures exposure across the interval, unlike a measure such as Cmax, which concerns the maximum observed concentration. The registry defines AUCtau for norelgestromin as the primary outcome and lists a mean and standard deviation as its summary statistics.

What does a mean and standard deviation describe?

The mean is the arithmetic average of the observed values in the analysis set. The standard deviation describes how dispersed those values are around the mean. These answer different descriptive questions: the mean concerns the central level, while the standard deviation concerns variability among observations. A mean and standard deviation do not by themselves show the uncertainty in a comparison or the precision of an estimated treatment-related change. The registry record does not report the primary endpoint’s mean or standard deviation values.

What would a comparison estimate add?

A drug-interaction question concerns how exposure under one drug condition relates to exposure under another condition. A comparison estimate expresses the size and direction of that relationship using an appropriate analysis of the study design. A confidence interval communicates the precision of an estimate by giving a range of values compatible with the data and analysis assumptions. It is not a guarantee that the true effect lies in the interval. The registry record does not report a primary endpoint contrast or confidence interval, so the effect and its precision cannot be described from the posted results.

Why does the design matter?

This record describes an open-label, single-group study with allocation listed as not applicable. It identifies Part A and Part B, but those labels should not be read as randomized parallel groups. The record does not describe a randomized control comparison. Interpretation of a pharmacokinetic contrast depends on the actual sequence of treatments, the measurements used in each condition, and the analysis model. The detailed protocol and statistical model are not reported in the registry record. As a result, the exact basis for any within-participant or between-participant comparison cannot be reconstructed from the record.

Open-label means masking is listed as none. For concentration-based pharmacokinetic outcomes, the outcome is a laboratory measurement, but that does not remove the need to understand collection, assay, handling, and analysis procedures. The registry record does not report enough detail to evaluate those procedures. It does list scheduled sampling at predose and multiple postdose times on Cycle 1, Study Day 14, and Cycle 2, Study Day 42.

How should the safety counts be understood?

The registry gives counts of participants at risk and counts who experienced serious or other adverse events. These are descriptive safety summaries. Counts alone do not adjust for duration of exposure, participant characteristics, or differences in observation. A comparison of counts across study parts would not automatically be a causal comparison, particularly when the record does not describe random assignment and does not clarify participant overlap between parts. The record lists zero serious adverse events in each group and zero deaths in each group; this does not establish that no unrecorded or unlisted events occurred outside the registry’s reported categories.

What do the sample-size assumptions mean?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. Such a calculation is a planning illustration, not observed power and not the trial’s own design justification. For non-time-to-event outcomes, the description says the results are participants per arm; time-to-event calculations instead use a total number of events. No numerical sample-size illustration results or trial-specific sample-size justification are reported in the registry record. The described two-arm illustration should not be confused with the actual single-group, non-randomized study design.

General statistical context: when data are more variable than a model assumes, standard errors and confidence intervals can be misleading unless the analysis accounts for that extra variability. This is the general reason over-dispersion matters. The registry record does not report an over-dispersion assessment or indicate that such a model was used. No claim about the study’s data distribution or model adequacy can therefore be made.

More broadly, statistical interpretation requires knowing the analysis population, outcome definition, missing-data handling, model, and contrast. The record defines the PK Analysis Set and primary endpoint, but does not provide the numerical primary results or a complete analysis plan. Without those details, readers can identify the intended measure and scheduled collection but cannot verify the primary estimate or reproduce its statistical interpretation.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Part A: NGM/EE", "Part B: NGM/EE + SOF/VEL/VOX + VOX")
n   <- c(15, 15)
m   <- c(13757.4, 14690.4)
sp  <- c(2478.44, 2116.43)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Part A: NGM/EE  15  13757.400  2478.440  12384.886  15129.914
CARM  Part B: NGM/EE + SOF/VEL/VOX + VOX  15  14690.400  2116.430  13518.360  15862.440

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 27 outcome measures and 11 analyses. It includes the primary norelgestromin AUCtau endpoint alongside other pharmacokinetic outcomes and safety outcomes, including treatment-emergent adverse events and laboratory abnormalities. The statistical plan for prioritizing or interpreting this collection of outcomes is not reported in the registry record. In particular, the record does not state whether a multiplicity adjustment was planned, which analyses were confirmatory, or how secondary analyses were to be interpreted. Without that information, the possibility of chance findings across multiple analyses cannot be assessed using the registry record alone.

The primary PK Analysis Set is defined as enrolled participants who took at least one dose of study drug and had at least one non-missing postdose plasma concentration value reported. This definition identifies who could contribute to the primary pharmacokinetic analysis, but does not specify the number included in that set or the number with complete AUCtau data. The handling of missing concentration measurements, incomplete profiles, protocol deviations, and participants without evaluable endpoint data is not reported in the registry record.

Enrollment was 15. The registry’s outcome and analysis listings do not provide a participant-flow account or explain the relationship between the Part A and Part B groups. A detailed statistical analysis plan, the sample-size justification, and rules for missing data are not reported in the registry record. These omissions limit assessment of analysis completeness, potential selection from the analysis-set definition, and the robustness of any result. Since the primary numerical result is also not reported, neither the estimated effect nor its precision can be evaluated.

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 non-serious adverse event terms

The registry reports safety counts for two groups. In Part A: NGM/EE, 15 participants were listed at risk for serious adverse events and none were listed as affected; 15 were listed at risk for other adverse events and 10 were listed as affected. In Part B: NGM/EE + SOF/VEL/VOX + VOX, 15 were listed at risk for serious adverse events and none were listed as affected; 15 were listed at risk for other adverse events and 14 were listed as affected. The record lists zero deaths in each group and no serious adverse-event terms.

These figures should be read as registry-reported counts, not as evidence that the groups are directly comparable. The study was open-label, single-group, and non-randomized; the registry record does not clarify whether participants in the two parts overlap or describe exposure duration for these summaries. The counts also do not show event severity beyond the serious-versus-other classification, timing, recurrence, or attribution to a particular study drug. The record does not report a causal assessment or a comparative statistical analysis of these safety counts. Zero serious events in the recorded groups is a descriptive observation and should not be interpreted as proof that serious events are impossible or that risks are equivalent between conditions.

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

The registry record identifies a drug-interaction question and describes how pharmacokinetic exposure was to be measured. The primary outcome was norelgestromin AUCtau, collected using scheduled plasma concentration measurements on Cycle 1, Study Day 14, and Cycle 2, Study Day 42. The record defines the PK Analysis Set and reports that the study was Phase 1, open-label, and single-group, with enrollment of 15.

What the record does not establish is the numerical result for the primary endpoint. It does not report the AUCtau mean, standard deviation, estimated contrast, or confidence interval. Consequently, the direction, size, and precision of any observed change in norelgestromin exposure are not reported in the registry record. The stated study aim is not itself a result, and no pharmacokinetic conclusion should be inferred from the aim or endpoint name.

The safety counts show that the registry listed no serious adverse events and no deaths in either reported group, while other adverse events were listed for 10 of 15 participants in Part A and 14 of 15 in Part B. These counts do not establish whether events were caused by a particular drug or whether the groups differ in safety. The registry design is not a randomized comparison, and the record does not clarify participant overlap between parts or give an adjusted analysis.

The record also does not report a full statistical analysis plan, missing-data rules, multiplicity approach, or sample-size justification. These details matter when judging how outcomes were selected, how incomplete concentration profiles were treated, and how precisely the primary question could be answered. The posted information supports a description of study intent, design features, endpoint definition, and recorded safety counts. It does not support a conclusion about the magnitude or clinical implications of a drug interaction.

14. Why This Trial Matters Statistically

This study is statistically relevant because drug-interaction research depends on careful definition of exposure and a design that supports a meaningful comparison across drug conditions. AUCtau is an exposure measure based on concentrations over a dosing interval, making the endpoint directly connected to the stated pharmacokinetic question. The scheduled sampling information and analysis-set definition help identify what the primary measure represents.

The record also illustrates why design labels need careful reading. Although Part A and Part B are listed, the study is described as single-group, open-label, and with allocation not applicable. Those features do not support treating the parts as randomized parallel groups. The record’s brief description mentions prior NGM/EE use as a basis for entering Part B, so the group labels should be interpreted in the context of study eligibility and sequence rather than as evidence of random assignment.

For statistical interpretation, outcome values and uncertainty are essential. The record identifies the primary endpoint but does not report its numerical results or a confidence interval. That gap prevents assessment of both the estimated exposure difference and its precision. Similarly, the adverse-event counts are useful descriptive information, but without participant-flow detail and a comparative analysis they cannot establish a causal safety contrast.

The record lists numerous outcomes and analyses but does not describe multiplicity handling or a full analysis plan. It also does not report the sample-size justification. These missing details limit the ability to evaluate whether the study was planned around a specific precision target, how secondary analyses should be interpreted, and how incomplete measurements were handled. The statistical importance of this record lies in distinguishing what the design and endpoint definitions tell readers from what requires numerical results and fuller analytic documentation.

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 registry record does not report numerical results for the primary AUCtau endpoint. There is no reported mean, standard deviation, estimated contrast, or confidence interval for norelgestromin. This is the central limitation for assessing the stated pharmacokinetic question: the endpoint and sampling schedule are described, but the result and its precision are not.

The design is listed as open-label and single-group, with allocation not applicable. The record describes Part A and Part B but does not provide a complete account of treatment sequence, participant overlap, or the basis for comparing their measurements. The detailed arm description is incomplete. These gaps make it inappropriate to infer a randomized control comparison or to treat the adverse-event group counts as a like-for-like estimate of treatment effect.

The registry record does not report the detailed statistical analysis plan, sample-size justification, multiplicity strategy, or missing-data rules. It defines the PK Analysis Set, but does not give the number included in that set or explain how incomplete concentration profiles were handled. It also does not provide enough information to assess the statistical model or verify the analysis.

Safety reporting is limited to counts at risk and counts affected, plus deaths and serious-event counts. The record does not report event-level detail for other adverse events, duration of exposure, or causal attribution. These limitations mean that safety counts remain descriptive and cannot establish comparative risk. More broadly, the registry entries identify the intended questions and selected design details but do not permit a full evaluation of pharmacokinetic effect, precision, or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate Effect of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination on the Pharmacokinetics of a Representative Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol — NCT02533427.
• Registry record last updated 2020-09-02; status last verified 2020-08.
• Results first posted 2020-09-02.
• 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

The registry record describes NCT02533427, a completed Phase 1, open-label drug-interaction study sponsored by Gilead Sciences, with enrollment of 15. The study assessed SOF/VEL/VOX plus VOX in relation to norgestimate/ethinyl estradiol pharmacokinetics. The primary endpoint was norelgestromin AUCtau, defined as exposure over the dosing interval, with scheduled concentration measurements on Cycle 1, Study Day 14, and Cycle 2, Study Day 42.

The design is listed as single group, with allocation not applicable and masking none. Safety listings report zero serious adverse events and zero deaths in each group, and other adverse events in 10 of 15 participants in Part A and 14 of 15 in Part B. The numerical primary endpoint results, confidence interval, detailed statistical plan, missing-data rules, and sample-size justification are not reported in the registry record. The posted information therefore supports description of the study’s aim and reported counts, but not an estimate of the primary pharmacokinetic effect.