Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive (NCT03984825), a na phase 1 study. The primary outcome is Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of EE.

2. Clinical Question

The clinical question is therefore a drug-interaction question: how contraceptive-drug exposure is characterized during the study sequence, and whether exposure differs when GSK3640254 is coadministered. The design description identifies a Portia-only period followed by a period with both drugs. Because the sequence was not randomized, it is not a like-for-like comparison between independently assigned groups. Any interpretation of a period contrast would need to account for the fixed order and the analysis actually used, which is not reported in the registry record.

The record gives the study rationale in the context of contraception for women with HIV, but the participants are described as healthy female subjects. It does not report pregnancy outcomes or establish contraceptive effectiveness. The question addressed is pharmacokinetic, not whether a clinical outcome such as pregnancy was prevented.

3. Trial Design

This was a completed phase 1, open-label, single-sequence, one-way drug-interaction study. The registry describes a single-group model, with allocation listed as not applicable and masking as none. Enrollment was 23. The study began on 2019-06-13 and primary completion was recorded as 2019-08-16.

The described sequence included a screening period of 28 days, check-in on Day -4, a run-in period, and treatment periods. Participants received Portia once daily during the run-in on Days -3 to -1, then Portia alone during treatment period A on Days 1 to 10. During treatment period B on Days 11 to 21, Portia was given with GSK3640254 200 mg once daily. The listed overall study duration was approximately 8 weeks, including screening and run-in.

There was no randomized allocation or masking. Portia alone was given before the combination period, so treatment condition and period order were linked. This design can describe pharmacokinetic measurements across the sequence, but it does not provide a randomized concurrent control group. Period-related changes or other time-linked influences cannot be separated from treatment condition unless addressed in the analysis; the analysis approach is not reported in the registry record.

The registry's arm description labels Portia as 0.3 mg EE/0.15 mg LNG, whereas the brief summary and detailed regimen description state 0.03 mg EE/0.15 mg LNG. The record therefore contains an inconsistency in the stated EE dose. The study is listed as completed, but the registry record does not establish from the information how many enrolled subjects completed each treatment period.

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: A total of 23 participants were enrolled in the study

Run-in Period (Day -3 to -1)

Treatment Period 1 (Day 1 to 10)

Reasons for not completing this period:

Treatment Period 2 (Day 11 to 21)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Population.

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.

6. Primary Endpoint

The registry lists the primary outcome as Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of EE, measured over Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours.

The primary endpoint is labeled as the Period 1 area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state (AUC [0-tau]) for ethinyl estradiol. Its unit is hour*picograms per milliliter. Blood sampling is listed for Day 10 at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, and 12 hours, and on Day 11 at 24 hours. The registry says pharmacokinetic parameters were calculated using standard non-compartmental analysis.

In general, AUC represents drug exposure across a specified time interval, incorporating concentration measurements over that interval rather than relying on a single measurement. For a drug-interaction study, exposure measures can help characterize whether the presence of another drug is associated with a change in drug levels. That is why AUC is commonly used in pharmacokinetic assessments.

The primary endpoint is summarized using a geometric mean and geometric coefficient of variation. In general, a geometric mean is useful for measurements that are positive and may be skewed, while the geometric coefficient of variation describes relative variability on a multiplicative scale. The registry defines the pharmacokinetic population as participants who underwent plasma pharmacokinetic sampling and had evaluable pharmacokinetic parameters estimated. The endpoint's numerical result and any uncertainty estimate are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes standard non-compartmental analysis for pharmacokinetic parameters and reports geometric means with geometric coefficients of variation for the primary measure. It does not provide a detailed statistical analysis plan, the primary estimate, or its uncertainty. The concepts below are general explanations of the methods named or relevant to interpreting the design, not claims about analyses that the registry record does not describe.

What does AUC measure?

In general, area under the concentration-time curve represents cumulative drug exposure over a defined interval. The AUC (0-tau) endpoint covers the interval from time 0 to the end of the dosing interval at steady state. Multiple blood samples across the interval are used to characterize the concentration profile. AUC is distinct from a peak concentration: it reflects the measured profile across time rather than only the highest observed value.

The registry specifies EE sampling on Day 10 at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, and 12 hours, and on Day 11 at 24 hours. In general, pharmacokinetic calculations depend on the available concentration measurements and the methods used to characterize the profile between samples. The record states that standard non-compartmental analysis was used, but does not give further calculation details or the resulting EE AUC value.

Why use a geometric mean?

In general, pharmacokinetic measures are often positive and can vary proportionally, so their distributions may be asymmetric on the original scale. A geometric mean summarizes such measurements by working with logarithms and returning to the original scale. It can be useful for describing a typical level when relative changes are more meaningful than additive changes.

A geometric coefficient of variation expresses variability relative to the geometric mean. It is not the same as a confidence interval: a coefficient of variation describes dispersion among observations, whereas a confidence interval describes uncertainty around an estimated quantity. The registry names the geometric coefficient of variation as the dispersion measure but does not report a confidence interval or other uncertainty interval for the primary endpoint.

What would a period comparison require?

In general, a drug-interaction assessment may compare exposure under a drug alone with exposure under coadministration. With repeated observations from the same participant, an analysis may account for the paired nature of the measurements. A ratio of geometric means is one common way to express relative exposure, but the registry record does not report that such a contrast was used, does not give an estimate, and does not state an analysis model. No result should be reconstructed from the regimen description alone.

The study sequence is fixed: Portia alone is followed by Portia with GSK3640254. In general, fixed sequence designs can be vulnerable to treatment-period differences because the treatment condition is not separated from order by randomization. A statistical model can address specified sources of variation only if they are measured and included as planned; the registry record does not describe whether period, sequence, or other covariates were modeled.

How should variability affect interpretation?

In general, pharmacokinetic data may be skewed, and the degree of variability influences how precisely an average or contrast is estimated. A geometric coefficient of variation gives descriptive information about relative spread. It does not, by itself, show whether an effect is clinically important, establish that two conditions are equivalent, or indicate how certain a contrast is. A confidence interval around a contrast would help show the range of values compatible with the data and the analysis, but such an interval is not reported for the primary outcome.

Over-dispersion is a general concern when observed variability is greater than a model's assumptions allow. If a method assumes less variability than is present, its uncertainty estimates may be too narrow. The registry does not report an over-dispersion assessment, a model-based variance estimate, or details that would support judging this issue for the trial. It is therefore a general consideration, not a finding about these data.

What do sample-size illustrations mean?

In general, sample-size planning asks how many participants would be needed under specified assumptions to detect an effect with a chosen statistical power. The registry's stated planning illustration uses the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These are illustration assumptions, not a report of the original trial's sample-size justification.

The record describes a single-group, fixed-sequence design rather than randomized equal allocation between two arms. Consequently, those illustration assumptions do not describe the trial's actual allocation structure. Planning estimates based on an observed effect are not observed power and should not be read as evidence that the study had a particular probability of finding an effect. The trial's own sample-size rationale is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 108 outcome measures and 0 analyses. Several secondary outcome descriptions concern progesterone, luteinizing hormone, follicle-stimulating hormone, and GSK3640254 pharmacokinetics. A large collection of outcomes can create multiplicity concerns: in general, testing many hypotheses can increase the chance of at least one apparently notable result unless the analysis plan accounts for the number and structure of comparisons.

The registry record does not report a multiplicity adjustment, a testing hierarchy, which outcomes were considered confirmatory, or how secondary outcomes were interpreted alongside the primary endpoint. It also does not report interim analyses. These items are not reported in the registry record, so no conclusion about how multiplicity was handled can be drawn.

The primary pharmacokinetic population is described as participants who underwent plasma PK sampling and had evaluable PK parameters estimated. This defines the population used for that endpoint, but the record does not state how many participants met the definition or how many had missing or unevaluable samples. The approach to missing measurements, exclusions, protocol deviations, or incomplete treatment periods is not reported in the registry record.

In general, missing pharmacokinetic samples can matter because measurements across the dosing interval contribute to estimating exposure. The effect of missingness depends on when samples are missing, why they are missing, and how the analysis handles them. No imputation method or sensitivity analysis is reported. The registry's outcome definitions alone do not establish whether missing data were absent or how any missing data were handled.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists three safety groups: Portia during the run-in, Portia during the period without GSK3640254, and Portia coadministered with GSK3640254. Serious adverse events are recorded as 0 in each group, and deaths are recorded as 0 in each group. Under other adverse events, the listed counts are 0 for run-in, 5 for Portia, and 9 for Portia with GSK3640254. The corresponding at-risk counts are 23, 23, and 21.

These are registry counts, not a statistical comparison. The sequence is not randomized, the periods are not like-for-like concurrent groups, and the at-risk counts differ across the listed periods. The record does not provide further event descriptions in the serious-event list; no serious-event terms are listed. The other-event counts do not establish severity, causality, or whether an event occurred in a particular participant more than once.

The dose label for the Portia safety group states 0.3 mg EE/0.15 mg LNG, while the regimen descriptions state 0.03 mg EE/0.15 mg LNG. This inconsistency is part of the registry record and should be kept in mind when reading the group labels.

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

The record establishes that a phase 1 study was conducted to investigate the pharmacokinetics of a combined oral contraceptive when given with GSK3640254. It describes a fixed sequence in which participants received Portia alone and then Portia with GSK3640254. It also identifies EE AUC (0-tau) as the primary endpoint and describes the blood-sampling schedule and pharmacokinetic population.

It does not establish the direction or size of a change in EE exposure. The numerical primary result, a comparison between treatment periods, and an uncertainty estimate are not reported in the registry record. Without those results, the extent and precision of any pharmacokinetic difference cannot be assessed from this record.

The study should not be interpreted as a randomized comparison of separate groups: it is listed as open-label, single-group, and single-sequence. The regimen order means that any period comparison would also involve a time-ordered sequence. The record does not describe an analysis that would separate a treatment association from all possible period-related influences.

The stated rationale concerns the importance of effective contraception for women with HIV, but the study population is described as healthy female subjects. The registry record does not report pregnancy outcomes or demonstrate contraceptive effectiveness. Pharmacokinetic measurements can inform drug exposure, but they are not themselves a clinical outcome.

The record also lists adverse-event counts, with no serious adverse events or deaths recorded in the groups. Those counts should be interpreted as descriptive registry entries, not as proof of absence of risk or as a comparative safety analysis. Overall, the available record describes the study question and methods, but not the results needed to assess the primary pharmacokinetic question.

13. Why This Trial Matters Statistically

This study illustrates why a clearly defined pharmacokinetic endpoint matters. AUC (0-tau) describes exposure over a dosing interval, while the geometric mean and geometric coefficient of variation provide a way to summarize typical exposure and relative variability. Those summaries can be useful in drug-interaction research, but they need an estimate and a measure of uncertainty to support interpretation. The registry identifies the endpoint but does not report its result.

The design also illustrates a distinction between a treatment sequence and a randomized comparison. Portia alone was given before the combination period, and the record lists a single group with no masking. This can allow repeated pharmacokinetic observations, but treatment condition and period order are linked. Statistical interpretation therefore depends on the analysis and its assumptions, which are not reported in the registry record.

The record's many listed outcome measures and absence of listed analyses highlight the importance of transparent reporting: readers need to know which outcome was analyzed, what contrast was estimated, how uncertainty was quantified, and how other outcomes were handled. An endpoint definition is not a substitute for a reported result.

Finally, the sample-size illustration assumptions differ from the described study structure. Distinguishing a planning illustration from the original design and from observed evidence prevents a hypothetical planning calculation from being mistaken for a trial result or a statement about observed power.

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 primary limitation for interpreting the study's main question is that the numerical primary outcome and its uncertainty are not reported in the registry record. The record gives an endpoint definition and sampling schedule, but no estimate that would show the magnitude or direction of EE exposure in Period 1, and no reported contrast between Portia alone and coadministration.

The design is open-label and single-sequence, with Portia alone preceding coadministration. There is no randomized concurrent comparator. Period and treatment condition are therefore linked, and the record does not report an analysis plan that would clarify how a period contrast was handled. Allocation is listed as not applicable, and masking as none.

The primary endpoint is labeled Period 1, while the study objective concerns the effect of coadministration. The record does not explain how the listed primary endpoint relates analytically to the treatment-period comparison. It also does not report confidence intervals, p-values, a multiplicity strategy, missing-data methods, or the original sample-size justification. The listed planning illustration uses equal allocation between two arms, which is not the described single-group sequence.

There is also an internal dose-label inconsistency: the arm description states 0.3 mg EE, while the brief summary and detailed regimen state 0.03 mg EE. The safety entries are descriptive counts across periods and do not constitute a randomized safety comparison. Finally, the record describes healthy female subjects; conclusions about other populations or clinical outcomes are not established by this study description.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive — NCT03984825.
• Registry record last updated 2020-08-27; status last verified 2020-08.
• Results first posted 2020-08-27.
• 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

NCT03984825 is a completed phase 1, open-label, single-sequence drug-interaction study sponsored by ViiV Healthcare. Enrollment was 23. The study began on 2019-06-13, with primary completion recorded on 2019-08-16.

Participants received Portia alone before receiving Portia with GSK3640254 200 mg once daily. The primary endpoint is EE AUC (0-tau) in Period 1, summarized by geometric mean and geometric coefficient of variation. The record defines the pharmacokinetic population and sampling schedule, but the primary numerical result and its uncertainty are not reported in the registry record.

The registry lists 108 outcome measures and 0 analyses. It records no serious adverse events and no deaths in the listed safety groups. The record contains an inconsistency in the stated Portia EE dose, and the sample-size assumptions describe a planning illustration rather than the original study design.