Evaluating Drug Interactions Between Doravirine With Estradiol and Spironolactone in Healthy Transgender Women: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluating Drug Interactions Between Doravirine With Estradiol and Spironolactone in Healthy Transgender Women (NCT04283656), a randomized phase 1 study. The primary outcome is Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞).

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, unmasked, three-period crossover interaction study. Its official title describes pharmacokinetic evaluation of doravirine and tenofovir disoproxil fumarate co-administered with hormonal therapy in adult HIV-negative transgender women. The registry lists the study as completed, with a recorded enrollment of 8. Six participants completed the study and were included in the pharmacokinetic analysis.

In a crossover design, participants receive more than one treatment condition, so comparisons can be made within participants rather than relying only on comparisons between separate groups. That feature can be useful for pharmacokinetic questions because each participant can contribute observations under multiple conditions. It also makes the sequence in which conditions are received relevant to interpretation. The registry labels the design as crossover and randomized, and describes three treatments. Details such as the treatment sequence allocation, any washout interval, and the handling of period or sequence effects are not reported in the registry record.

The primary comparison was between Treatment C, a single dose of doravirine/lamivudine/tenofovir disoproxil fumarate co-administered with estradiol and spironolactone, and Treatment A, a single dose of doravirine/lamivudine/tenofovir disoproxil. Treatment B was single-dose estradiol and spironolactone co-administered with placebo. The listed hormone doses were estradiol 2mg and spironolactone 100mg. The record does not give further dosing or timing details beyond the descriptions of these treatment conditions.

The study start is recorded as 2022-01-04 and primary completion as 2022-10-25. Enrollment is not the same as the number included in the primary pharmacokinetic analysis: the registry separately identifies the 6 study completers included in that analysis. Reasons for non-completion and the treatment of data from participants not included in the analysis are not reported in the registry record. The record also does not report details of the randomization procedure, masking procedures beyond stating none, or a statistical analysis plan.

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: 8 enrolled participants were randomized 1:1 to either Sequence E of F.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 6 participants completed the study and were included in the pharmacokinetic analysis.

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: 8 participants were enrolled in the study and randomized 1:1 to either Sequence E or F.

6. Primary Endpoint

The registry lists the primary outcome as Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞), measured over Pre-dose, 0.5, 1, 2, 6, 12, 24, 48, 72, 96 hours post-dose for all participants.

The primary endpoint was doravirine area under the plasma concentration versus time curve from 0 hours to infinity, abbreviated AUC0-∞. It represents an aggregate measure of drug exposure over time: plasma concentrations are observed after dosing, and the area under the concentration-time profile is used to capture exposure across the measured period and its extrapolation to infinity. The registry lists the unit as hr*ng/mL and describes the endpoint as a geometric mean.

For this study, plasma sampling was scheduled pre-dose and at 0.5, 1, 2, 6, 12, 24, 48, 72, and 96 hours post-dose for all participants. Measuring concentrations at multiple time points supports the estimation of the concentration-time profile, from which the AUC can be derived. AUC is used in pharmacokinetic interaction studies because a change in exposure can indicate that co-administration alters the amount of drug reaching the systemic circulation over time. That is a pharmacokinetic question, not a direct measure of a clinical outcome.

The registry describes a geometric mean ratio comparison between treatment arms. The reported ratio of 0.97 compares doravirine exposure under Treatment C with exposure under Treatment A. The confidence interval communicates uncertainty in that relative estimate. The registry does not report the specific equivalence margins, the full method used to estimate the AUC, or a p-value for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the geometric mean ratio represent?

A geometric mean is commonly used for pharmacokinetic measurements because exposure values often vary multiplicatively rather than by equal additive increments. The geometric mean is calculated on a logarithmic scale and then expressed on the original scale. A geometric mean ratio compares the exposure summaries for two treatment conditions. A ratio of 1 represents equal summaries; values below or above 1 represent lower or higher exposure in the numerator condition relative to the denominator condition. This is a general statistical explanation. In this study, the reported geometric mean ratio is 0.97 for Treatment C compared with Treatment A.

The ratio should not be read as an individual participant’s change. It is a summary comparison across the analyzed participants. The registry lists 6 participants for each of the two treatment summaries and says that 6 participants completed the study and were included in the pharmacokinetic analysis. Because this is a crossover study, participants contributed to treatment conditions, rather than the two treatment summaries necessarily representing separate groups of people.

What does the confidence interval say?

A confidence interval gives a range of values that are compatible with the observed data under the statistical model and its assumptions. It conveys the precision of an estimate: a narrower interval indicates greater precision, while a wider interval indicates greater uncertainty. A confidence interval is not a range that contains a fixed proportion of individual participant values, and it does not describe the probability that the true value lies inside the particular interval after the data have been observed. These are general interpretations of confidence intervals.

The registry reports a 90% confidence interval from 0.76 to 1.24 for the geometric mean ratio. Those limits place the interpretation in context: the ratio estimate is not known with high precision. The registry does not report the model details, variance estimates, or other information needed to reproduce the interval independently.

Why use an equivalence framework?

Equivalence analysis asks whether an estimated difference or ratio is sufficiently close to a prespecified reference value, using margins that define what counts as an acceptably small difference. It is not enough for a result to be statistically non-significant in a conventional difference test; the interval must be assessed against the stated equivalence margins. This is general statistical guidance. The registry labels the reported analysis as equivalence and provides a 90% interval, but the equivalence margins and the formal decision rule are not reported in the registry record. Without them, the reported interval cannot be used to determine whether the study met its equivalence criterion.

What does crossover randomization contribute?

Randomization can help allocate participants to treatment sequences without systematic selection. In a crossover design, each participant receives multiple conditions, allowing a within-participant comparison. Since people differ in their underlying pharmacokinetics, within-participant comparisons can reduce the influence of stable differences between people. This is a general design advantage, not a guarantee that all sources of bias or variation are removed.

Crossover studies also require attention to period effects, treatment sequence, and possible carryover from one condition into a later period. A washout interval can be relevant when the effect of an earlier treatment could persist, but the registry record does not report whether or how a washout was used. Details of period and sequence adjustment, and the randomization procedure, are also not reported. The adverse-event results are listed by sequence, but those safety summaries do not supply the missing information about the primary pharmacokinetic model.

How should geometric variability be understood?

The registry reports a geometric coefficient of variation for each treatment summary: 21.7 for Treatment C and 41.75 for Treatment A. A coefficient of variation expresses variability relative to a mean; a geometric version is suited to measurements analyzed on a multiplicative scale. More variability generally means less precision in an estimate when other design features are held constant. This is a general explanation, not a recalculation of the study results. The registry does not provide the complete statistical model or enough detail to reconstruct how these variability summaries entered the confidence interval.

Why is the sampling schedule relevant?

AUC summarizes exposure over a time course, so its estimation depends on concentration measurements taken at multiple times. The registry lists pre-dose sampling and post-dose sampling at 0.5, 1, 2, 6, 12, 24, 48, 72, and 96 hours. More generally, the concentration profile between observed times and the portion extrapolated beyond the last observation can affect an AUC estimate. The endpoint title specifies AUC from 0 hours to infinity, but the registry does not report the calculation details, the fraction extrapolated, or participant-level concentration data.

The registry lists 9 outcome measures and 9 analyses, while no secondary outcome measures are posted. The relationship among the listed measures and analyses, the full analysis plan, and any adjustment for multiple statistical tests are not reported. In general, when several outcomes or analyses are examined, multiplicity can increase the chance of highlighting a result that appears notable by chance. Whether and how that issue was addressed in this study is not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the primary comparison as an equivalence analysis, with a geometric mean ratio of 0.97 and a 90% confidence interval from 0.76 to 1.24. It does not report a p-value, the equivalence margins, or the complete statistical procedure. Those omissions limit how fully the sponsor’s analysis can be evaluated from the registry entry alone.

The posted arm summaries are geometric mean AUC values of 17800.0 hr*ng/mL for Treatment C and 18410.0 hr*ng/mL for Treatment A. A separate re-calculated estimate is not available in the registry record. The reported ratio and interval should therefore be read as the registry’s analysis, not as a result independently reconstructed from participant-level data.

The equivalence label is informative about the stated analysis framework, but it does not by itself establish that the formal equivalence requirements were met. Such a conclusion requires the prespecified margins and decision rule, which are not reported in the registry record. The sponsor’s analysis is the relevant posted result; its interpretation should remain limited to the information and uncertainty reported with it.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures and 9 analyses, and identifies the doravirine AUC0-∞ comparison as the primary outcome. It reports no secondary outcome measures. The record does not explain how the listed measures and analyses relate to one another, whether they were all prespecified, or whether additional analyses were conducted but not posted.

Multiplicity arises when statistical conclusions are drawn from several outcomes, comparisons, or analyses. Considering many results can make chance findings more likely to attract attention. Common approaches include prespecifying a primary outcome, limiting confirmatory comparisons, or adjusting inference to account for multiple testing. These are general statistical concepts. Whether any such approach was used beyond identifying the primary endpoint is not reported in the registry record.

The registry does not report an analysis plan, a multiplicity adjustment, or interim analyses. It also does not report a p-value for the primary comparison. As a result, the primary interpretation rests on the reported ratio and confidence interval, while the broader set of listed measures cannot be fully assessed for selective reporting or multiplicity from the registry information alone.

The record states that 8 participants were enrolled and that 6 completed the study and were included in the pharmacokinetic analysis. The reasons for non-completion, whether data were missing at particular time points, and how any missing observations were handled are not reported in the registry record. The analysis population is described for the primary pharmacokinetic outcome, but the registry does not provide a detailed definition of the analysis set or explain whether other populations were considered.

These reporting gaps matter because missing data and analysis-set choices can affect both the estimate and its uncertainty. In a crossover study, incomplete participation can also affect which treatment comparisons are available. The record does not give enough detail to determine the extent or handling of any such effects. These limits do not invalidate the posted estimate, but they constrain how completely it can be independently 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events by treatment sequence. For Sequence E, 0 serious events are recorded among 4 participants at risk; for Sequence F, 0 serious events are recorded among 4 participants at risk. No deaths are listed in either sequence. The registry also records 4 participants with other adverse events in each sequence, among 4 at risk in each sequence.

These are descriptive counts in a small study, not a comparative estimate of safety risk. The record does not list serious adverse-event terms, and the top serious-event terms field is empty. The category described as other adverse events should not be confused with serious adverse events: the listed counts distinguish the two categories.

In a crossover study, participants may contribute safety observations across treatment periods or sequences. The registry’s sequence-level summary does not provide detailed event timing, duration, severity for non-serious events, attribution, or a treatment-by-treatment breakdown. Those details are not reported in the registry record. The absence of recorded serious events in these summaries should therefore be read as a description of the posted observations, not as proof that serious events cannot occur or that a treatment is safe.

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

The result provides a focused estimate of doravirine exposure under the study’s specified single-dose conditions. The registry reports a geometric mean ratio of 0.97 for Treatment C compared with Treatment A, with a 90% confidence interval from 0.76 to 1.24. The central estimate is near 1, but the interval is broad enough to leave meaningful uncertainty about the relative exposure comparison.

This is a pharmacokinetic result, not a finding about clinical effectiveness or long-term safety. AUC describes drug exposure over time; it does not directly measure HIV treatment outcomes, hormone-related outcomes, or participants’ experiences of care. The registry’s background identifies the potential relevance of interactions between antiretroviral drugs and gender-affirming hormonal therapy, but this particular primary endpoint addresses drug exposure under the tested conditions.

The study involved adult HIV-negative transgender women, and the primary analysis included 6 participants who completed the study. The registry records enrollment of 8. The result should not be assumed to describe every transgender woman, people with HIV, different doses, prolonged co-administration, or treatment settings not represented by the stated study conditions. Details about those settings are not reported in the registry record.

The equivalence label requires care in interpretation. Formal equivalence depends on prespecified limits and a decision rule; the registry does not report those limits. The ratio and confidence interval alone therefore do not establish that the study demonstrated equivalence. Nor does the lack of a reported p-value establish that there is no interaction. The defensible interpretation is narrower: the posted analysis estimates relative doravirine AUC for the two treatment conditions and communicates uncertainty around that estimate.

In short, the posted result is useful as a small pharmacokinetic comparison, but its precision, population, dosing conditions, and incomplete reporting should guide how far it is interpreted. It does not settle questions about long-term co-administration or clinical outcomes.

14. Why This Trial Matters Statistically

This trial illustrates why interaction studies often focus on pharmacokinetic measures. When two therapies may influence drug metabolism or exposure, measuring concentrations over time can help characterize whether exposure differs under co-administration. The study’s stated focus was the potential bidirectional interaction between doravirine and hormonal therapy involving estradiol and spironolactone. Its primary endpoint, AUC0-∞, addresses one part of that question by summarizing doravirine exposure.

The crossover structure is also statistically relevant. A within-participant comparison can reduce the influence of stable differences between participants, which can be helpful when the available study population is limited. At the same time, crossover results depend on treatment periods and sequences, and interpretation can be affected by carryover or incomplete participation. The registry identifies a randomized crossover design but does not report enough methodological detail to assess all of these features.

The reported ratio and confidence interval demonstrate why an estimate should be read together with its precision. A point estimate alone can seem decisive, while its confidence interval may reveal substantial uncertainty. Here, the registry reports a 90% interval from 0.76 to 1.24. The equivalence framing also highlights the importance of prespecified margins: a ratio near 1 does not, by itself, establish equivalence.

Finally, the distinction between enrollment and the analyzed population matters. The registry records enrollment of 8 and identifies 6 completers in the pharmacokinetic analysis. Those details, together with the missing information about analysis methods and missing data, define the limits of what can be inferred. The trial is statistically instructive because it connects design, endpoint choice, uncertainty, and reporting completeness in a narrowly focused interaction question.

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 primary limitation for interpretation is the size of the analyzed population: the registry states that 6 participants completed the study and were included in the pharmacokinetic analysis. Enrollment was recorded as 8, but reasons for non-completion and the handling of unavailable data are not reported in the registry record. With a limited analysis population, estimates may be sensitive to individual observations, and the confidence interval appropriately remains central to interpretation.

The registry identifies a randomized, unmasked, three-period crossover design, but does not report the randomization procedure, treatment sequence details, washout information, or the statistical handling of period and sequence effects. Those details are especially relevant to interpreting crossover pharmacokinetic results. The record also does not report the full AUC calculation method, participant-level data, or the amount of extrapolation used for AUC0-∞.

The reported equivalence analysis lacks its stated margins and decision rule in the registry entry. Without those, readers cannot independently assess whether the interval satisfied the formal equivalence criterion. The record also lacks a p-value and a detailed statistical analysis plan. Although 9 outcome measures and 9 analyses are listed, the relationship among them and any adjustment for multiple comparisons are not reported.

The study evaluates specified single-dose conditions in adult HIV-negative transgender women. It does not directly provide evidence about long-term dosing, clinical outcomes, or groups and conditions not represented in the record. These limitations constrain the scope and precision of interpretation; they do not change the reported ratio or its confidence interval.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluating Drug Interactions Between Doravirine With Estradiol and Spironolactone in Healthy Transgender Women — NCT04283656.
• Registry record last updated 2025-03-26; status last verified 2025-03.
• Results first posted 2025-03-26.
• 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 describes a completed Phase 1 randomized, unmasked, three-period crossover interaction study of doravirine with estradiol and spironolactone in adult HIV-negative transgender women. Enrollment was recorded as 8, and 6 participants completed the study and were included in the primary pharmacokinetic analysis.

The primary endpoint was doravirine AUC0-∞. The posted geometric mean ratio for Treatment C versus Treatment A is 0.97, with a 90% confidence interval from 0.76 to 1.24. The registry labels the analysis as equivalence, but does not report the equivalence margins or full analysis details. The result is best understood as a pharmacokinetic estimate with uncertainty, not as a clinical outcome or a complete assessment of long-term co-administration.