Protease Inhibitors and Combined Oral Contraceptive Pharmacokinetics and Pharmacodynamics: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Protease Inhibitors and Combined Oral Contraceptive Pharmacokinetics and Pharmacodynamics (NCT02531321), a non-randomized phase 4 study. The primary outcome is Levonorgestrel Area Under the Curve.

2. Clinical Question

The research question links a pharmacokinetic measure of hormone exposure to a pharmacodynamic measure of ovulation. The brief summary says investigators hypothesized that levonorgestrel exposure would be increased with ritonavir, ethinyl estradiol exposure would be decreased, and ovulation would be unchanged. Those statements describe hypotheses, not findings. The registry record does not report group-level results for these outcomes, so it cannot establish whether the observed data aligned with those expectations.

The comparison is observational rather than randomized: participants were grouped according to their existing antiretroviral regimens. This means the central question is a comparison between groups with different regimen use, not a randomized estimate of the effect of assigning ritonavir. The registry record does not report further information about group comparability or adjustment for differences between participants. Accordingly, the clinical question and any interpretation of a contrast need to remain tied to this study's non-randomized design.

3. Trial Design

The registry describes a prospective, two-arm cohort and pharmacokinetic study in HIV-positive women. One group took an antiretroviral regimen including ritonavir-boosted protease inhibitors; the control group took regimens described as known not to interact with combined oral contraceptives. The study is listed as Phase 4, non-randomized, unmasked, and parallel. Its status is terminated, and the registry lists enrollment as 17.

Both groups were to take a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol for 21 days. The brief summary describes twice-weekly serum progesterone measurements during this period and a pharmacokinetic study on the final day. The primary outcome is levonorgestrel area under the curve from 0 to 72 hours, with a listed timeframe of 24 days. The registry also lists ethinyl estradiol area under the curve and serum progesterone as secondary outcomes.

Because allocation was non-randomized, the arms are not a like-for-like control comparison by design. Antiretroviral regimen determines group membership in the description, and the registry record does not report a random assignment procedure. Masking is listed as none. The record does not report whether outcome measurement or analysis was conducted by people unaware of group membership.

The registry lists the study start as 2015-08 and primary completion as 2016-11. It does not report a reason for termination in the information available in the registry record. Nor does the record state whether recruitment, follow-up, and outcome collection were completed as initially intended. Enrollment as listed should not be treated as proof that every enrolled participant contributed data to every outcome.

4. Participant Flow and Accounting

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

Overall Study

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 Levonorgestrel Area Under the Curve, measured over 24 days.

The primary endpoint is levonorgestrel area under the curve from 0 to 72 hours, reported as a mean with standard deviation and measured in ng/mL*h. Area under the curve (AUC) summarizes concentration over time: it reflects both the level of the drug or hormone in the sampled blood and how that level changes across the measurement interval. In general, it is a pharmacokinetic measure of exposure, not a direct measure of ovulation or contraceptive outcome.

Comparing AUC between the ritonavir and control groups was intended to assess whether levonorgestrel exposure differed with the antiretroviral regimen group. The registry summary states that increased levonorgestrel levels in the ritonavir group were hypothesized, but this is not an observed result. The registry record does not report group means, standard deviations, an estimated contrast, or a confidence interval for the primary endpoint.

The listed outcome timeframe is 24 days, while the endpoint description specifies an AUC from 0 to 72 hours and the study summary describes 21 days of contraceptive use followed by pharmacokinetic assessment on the final day. These describe different aspects of timing: the outcome's listed timeframe and the concentration interval used for its AUC. The registry record does not explain the timeframe further. It also does not report the sampling schedule or details of how AUC was estimated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies levonorgestrel AUC as a continuous outcome summarized by a mean and standard deviation. A continuous measure can take values across a scale rather than being restricted to categories such as yes or no. Here, the measurement is an exposure summary in ng/mL*h, calculated conceptually from hormone concentration over the interval from 0 to 72 hours. The registry record does not report the observed mean or standard deviation in either group.

What does the mean describe?

In general, a mean is the arithmetic average of the observed measurements in a group. It provides a central summary, but does not show how individual measurements are distributed. The standard deviation describes the spread of observations around the mean. A mean without a measure of spread does not fully convey how variable the data are; a standard deviation without the group size and outcome details is also insufficient to assess the uncertainty of the mean.

For this study, the primary endpoint is specifically levonorgestrel AUC from 0 to 72 hours. The study summary describes a pharmacokinetic assessment on the final day of contraceptive use. The registry record does not report the concentration sampling times, the method used to estimate AUC, or how measurements below any assay threshold were handled. Those details matter in general because the AUC estimate depends on observed concentrations and the method used to connect measurements over time.

What is the group comparison?

The intended comparison is between participants taking ritonavir-containing antiretroviral regimens and participants taking regimens described as known not to interact with oral contraceptives. Since allocation is non-randomized, this is a comparison of groups formed by existing regimen use. In general, a difference in group means describes the observed contrast in average outcome; it does not by itself show that the regimen caused the contrast. Other differences between groups can influence an unadjusted comparison.

The registry record does not report an adjusted model, covariates, or an analysis plan for the primary outcome. It also does not report a primary outcome estimate or a standard error. Consequently, a reader cannot determine from this record whether the comparison was adjusted, how uncertainty was quantified, or whether the analysis followed a prespecified model.

Why does variability matter?

General statistical explanation: biological measurements can vary between people and within a person over time. Greater variability makes it harder to distinguish a group difference from variation in the measurements, all else being equal. In pharmacokinetic studies, concentration profiles contribute to the AUC, and the observed spread of AUC values is relevant to the precision of a group estimate. The record's designation of standard deviation indicates a planned summary of spread, but the actual standard deviations are not reported in the registry record.

Over-dispersion is a general concern when data vary more than a model assumes. If a model understates variability, estimated uncertainty can be too small and statistical evidence can appear stronger than warranted. This concept is especially relevant to outcomes modeled as counts or binary events, where a model makes assumptions about how observations vary. The primary outcome is continuous, but the secondary ovulation outcome is described through progesterone measurements and a threshold. The registry record does not identify the model used for that secondary outcome or report an over-dispersion assessment.

What can a confidence interval tell a reader?

In general, a confidence interval expresses uncertainty around an estimated effect under the assumptions of the statistical method. Its location indicates which effect values are compatible with the data and model, and its width indicates precision. A confidence interval is not a guarantee that the true effect lies within the particular interval. For this study, no confidence interval for levonorgestrel AUC is reported in the registry record, so neither the range of compatible effects nor the precision can be described.

A p-value, in general, measures how incompatible data are with a specified null hypothesis under the assumptions of a test. It does not measure the probability that the null hypothesis is true, and it does not indicate the size or clinical importance of an effect. No p-value for the primary comparison is reported in the registry record. There is therefore no basis in the registry record to describe the primary result as statistically significant or not statistically significant.

How should planning illustrations be read?

The planning assumptions describe illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is specified as a fraction of the observed effect. Such calculations are planning illustrations, not observed power. In general, they show what sample size might be required under stated assumptions, rather than measuring the probability that the completed study detected an effect. The registry record does not report the observed primary effect needed to interpret the numerical planning illustrations, nor does it report the trial's own sample-size justification.

The registry's analysis count is listed as 1, but this alone does not identify the statistical method, analysis population, or handling of missing measurements. The analysis method and model assumptions are not reported in the registry record. Statistical interpretation should therefore be limited to the endpoint definition and design information that the record states, without assuming unreported procedures.

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("Ritonavir", "Control")
n   <- c(5, 10)
m   <- c(321, 243)
sp  <- c(61, 83)
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  Ritonavir  5  321.000  61.000  245.258  396.742
CARM  Control  10  243.000  83.000  183.625  302.375

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and one analysis. It identifies levonorgestrel AUC as the primary outcome and names ethinyl estradiol AUC and serum progesterone reflecting ovulation as secondary outcomes. The registry record does not report a multiplicity adjustment, a hierarchy among the outcomes, or a plan for controlling the chance of false-positive findings when several outcomes are examined. It also does not report whether additional analyses were conducted.

In general, multiplicity arises when multiple hypotheses or outcomes are tested. If each is assessed separately, the chance of at least one apparently unusual result can increase. Statistical methods can address this concern, but the method and any prespecified decision rules are not reported in the registry record. No claim about multiplicity control can be made from the number of listed analyses alone.

The record does not report missing-data counts, reasons for missing measurements, or methods for handling missing data. It also does not define an analysis population for the primary outcome, such as whether the analysis included everyone enrolled or only participants with usable pharmacokinetic measurements. The listed enrollment of 17 is not enough to establish the number contributing to each endpoint. Group-specific denominators for the primary and secondary outcome analyses are not reported in the registry record.

In general, missing outcome data can affect both the precision and potential representativeness of an estimate, especially if the likelihood of missingness is related to participant characteristics or outcome values. Without information on completeness and handling, the direction or scale of any such effect cannot be assessed. The reason for termination and its relationship, if any, to outcome availability are also not reported in the registry record.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The adverse-event listing reports 0 serious adverse events among 7 at risk in the ritonavir group and 0 among 10 at risk in the control group. For other adverse events, it reports 0 among 7 at risk in the ritonavir group and 0 among 10 at risk in the control group. The registry record lists no top serious-event terms. The deaths entries are null, so death counts are not reported in the registry record.

These figures describe the event counts captured in the registry record and should not be interpreted as proof that no adverse events occurred outside the reported categories or observation period. The record does not provide further detail about event definitions, surveillance procedures, duration of safety follow-up, or whether all participants contributed to safety follow-up. The at-risk counts shown for safety are not necessarily the denominators for the pharmacokinetic or progesterone outcomes.

In general, a zero count in a study does not establish that an event is impossible or that the groups have identical safety profiles. The amount of information in an event count depends on the number followed and how events were collected. The non-randomized design also means these safety counts are not a randomized comparison. They are descriptive figures from the two regimen groups, not estimates of a causal safety effect.

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

The study was designed to compare levonorgestrel and ethinyl estradiol pharmacokinetics, and ovulation-related progesterone measurements, between HIV-positive women taking different antiretroviral regimens. Its primary endpoint is levonorgestrel AUC from 0 to 72 hours. The registry record states the study hypotheses and endpoint definitions, but does not report primary or secondary outcome values. It therefore does not show the magnitude, direction, or precision of an observed outcome contrast.

The distinction between a hypothesis and a result is essential. The brief summary says investigators expected levonorgestrel levels to increase with ritonavir, ethinyl estradiol levels to decrease, and ovulation to be unchanged. These are expectations specified in the study description. They do not establish that any of those patterns occurred.

The study's non-randomized design also defines what a comparison can mean. In general, observed differences between groups can reflect both regimen use and other group differences. The registry record does not report adjustment methods or enough baseline information to determine how potential confounding was handled. A contrast should not be interpreted as the causal effect of assigning a regimen solely from the design information available.

The record also does not permit conclusions about the clinical consequences of any pharmacokinetic difference. AUC is an exposure measure, while the progesterone outcome is intended to reflect ovulation according to the study's description. The registry record does not provide evidence connecting the measured exposure to a clinical outcome, and the outcome results themselves are not reported.

Accordingly, the record supports a description of the research question, study procedures, and limited safety counts, but not a conclusion that one regimen group had higher or lower hormone exposure or different ovulation findings. Missing outcome estimates, uncertainty measures, analysis details, and information about missing data prevent a fuller statistical interpretation.

14. Why This Trial Matters Statistically

This study is statistically notable for connecting pharmacokinetic measurements with a pharmacodynamic outcome in a non-randomized clinical comparison. Levonorgestrel and ethinyl estradiol AUC summarize hormone exposure over time, while repeated serum progesterone measurement was intended to assess ovulation. The design therefore posed more than a simple comparison of concentrations: it sought to relate pharmacokinetic changes to a biological outcome.

The two groups were defined by antiretroviral regimen rather than random assignment. This is important for statistical interpretation because group contrasts in a prospective cohort may be influenced by differences between participants in addition to regimen use. The registry record does not describe adjustment for such differences. Recognizing this design feature helps separate an observed association from a causal effect.

The study also illustrates why outcome definitions and reporting matter. The primary endpoint is specified as levonorgestrel AUC from 0 to 72 hours, and the record gives a summary measure and unit. However, without group estimates and measures of uncertainty, readers cannot assess the size or precision of the contrast. A clearly defined endpoint is necessary for interpretation, but it cannot substitute for posted outcome results.

The record describes progesterone monitoring and lists a threshold-based secondary outcome. There is a wording and unit inconsistency: the secondary outcome title says serum progesterone greater than 3ng/dL, while the brief summary defines ovulation using serum progesterone of at least 3 ng/mL. The registry record does not clarify this difference. That ambiguity matters because thresholds and units are part of an outcome's operational definition.

Finally, the termination status, limited outcome reporting, and absence of analysis details constrain what can be learned statistically. The study question remains clearly described, but the registry record does not supply the estimates needed to evaluate the hypotheses or the precision of the findings.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main trial-specific limitation for interpretation is the absence of reported efficacy outcome results. The registry record does not report levonorgestrel AUC means or standard deviations, an estimated group contrast, or uncertainty measures. It also does not report the ethinyl estradiol or progesterone results. The planned comparison can be described, but the outcome findings cannot be assessed from the record.

Group assignment was non-randomized, and the registry explicitly describes the arms as not being a like-for-like control comparison. The record does not report baseline characteristics, adjustment variables, or an adjusted analysis. It is therefore not possible to evaluate how comparable the groups were or whether potential confounding was addressed.

The record lists enrollment as 17, but does not report how many participants contributed usable data to each outcome or whether the listed enrollment represents the number with completed measurements. Missing-data amounts, reasons, and handling methods are not reported in the registry record. The status is terminated, but the reason and any consequences for recruitment, follow-up, or outcome collection are not stated.

There is also ambiguity in the progesterone outcome definition: the secondary outcome title uses greater than 3ng/dL, whereas the brief summary describes a threshold of at least 3 ng/mL. No clarification is reported. The record lists a 24-day timeframe for the primary endpoint while describing 21 days of contraceptive use and an assessment on the final day; it does not further explain the timeframe. These details limit the ability to reproduce or precisely interpret the endpoint from the registry description.

Finally, methods for estimating AUC, statistical models, confidence intervals, multiplicity handling, and analysis populations are not reported in the registry record. These omissions restrict evaluation of analytic assumptions and result precision.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Protease Inhibitors and Combined Oral Contraceptive Pharmacokinetics and Pharmacodynamics — NCT02531321.
• Registry record last updated 2019-05-31; status last verified 2019-05.
• Results first posted 2019-05-31.
• 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 Phase 4, prospective, non-randomized, parallel, two-arm study in HIV-positive women, with no masking. Participants took a combined oral contraceptive containing 150mcg levonorgestrel and 30mcg ethinyl estradiol while using either ritonavir-containing antiretroviral regimens or regimens described as not interacting with oral contraceptives. Enrollment is listed as 17; the study status is terminated.

The primary endpoint is mean levonorgestrel AUC from 0 to 72 hours, with standard deviation, measured in ng/mL*h. The registry record does not report the primary endpoint results or results for the listed secondary outcomes. Safety listings show 0 serious and 0 other adverse events in each group, with deaths not reported. The record does not report the reason for termination, outcome-specific denominators, missing-data handling, or the statistical analysis details needed to assess the precision of the intended group comparisons.