PK Study of Rifampicin Interactions With DMPA and Efavirenz in TB: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PK Study of Rifampicin Interactions With DMPA and Efavirenz in TB (NCT02412436), a na phase 2 study. The primary outcome is Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12.

2. Clinical Question

The central statistical question is about a threshold-based pharmacokinetic endpoint, not a treatment-versus-control contrast. The registry description states that suppression of ovulation generally occurs while the DMPA level is at least 0.1 ng/mL. The primary endpoint therefore counts participants whose concentration falls below that threshold at the specified time point. It does not directly report whether an individual ovulated, nor does it directly estimate a comparative effect against another contraceptive regimen.

The registry also identifies questions about how frequently DMPA should be given in women taking these HIV and tuberculosis medicines and whether the medicines can be taken at the same time. Those broader questions require careful interpretation: the listed design has a single DMPA group and no randomized control group. The primary endpoint estimate itself is not reported in the registry record, so the posted record does not give a numerical answer to the Week 12 threshold question.

3. Trial Design

This was a Phase 2, open-label, non-randomized, single-group study with 62 enrolled participants. The study focused on pharmacokinetic interactions among DMPA, RIF, and EFV in women co-infected with HIV and tuberculosis. The brief description says participants were taking EFV, RIF, and INH. At study entry, designated week 0, participants received one 150 mg intramuscular dose of DMPA together with RIF and EFV.

Because the study had one group, it did not assign participants to different DMPA schedules or to a separate control treatment in the design described by the registry. There was no masking. A single-group study can describe concentrations and outcomes observed over follow-up in that group, but it cannot by itself separate the effect of one co-administered medicine from the effects of the others, or from changes over time. It also does not provide a randomized estimate comparing one schedule with another.

The registry lists the study status as completed. Its primary endpoint is the percentage of participants with plasma DMPA concentrations below 0.1 ng/mL at Week 12, calculated with an exact Clopper-Pearson 95% confidence interval. Participants without DMPA concentrations at weeks 10 and 12 were excluded from that analysis. Secondary outcomes include threshold-based concentration measures at earlier weeks, pharmacokinetic measures such as AUC, Cmin, Cmax, apparent clearance and half-life, and the occurrence of Grade 3 or higher signs, symptoms, or laboratory abnormalities.

The registry record does not report the protocol’s sample-size justification, detailed visit schedule beyond the stated time points, or a complete statistical analysis plan. The listed design details therefore support a description of the planned group and endpoint, but not assumptions about unreported procedures.

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: Of the 85 women screened, 62 were deemed eligible and enrolled into this single-arm study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the 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: All enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12, measured over Week 12.

The primary endpoint is the percentage of participants whose plasma DMPA concentration was below 0.1 ng/mL at Week 12. It converts each eligible participant’s measured concentration into one of two categories: below the threshold or not below it. The endpoint is reported as a percentage, with an exact Clopper-Pearson 95% confidence interval specified in the registry.

The threshold is used because the registry description says that suppression of ovulation generally occurs as long as the DMPA level is at least 0.1 ng/mL. A concentration below that level is therefore a pharmacokinetic marker of interest in the study’s stated question about DMPA exposure during EFV and RIF use. It is not itself a direct observation of ovulation, pregnancy, or contraceptive failure. Those clinical outcomes should not be inferred solely from a measured drug concentration.

The analysis population is restricted: participants without DMPA concentrations at weeks 10 and 12 were excluded. The registry record does not report how many participants were excluded, the number meeting the threshold, the resulting percentage, or the confidence interval limits. As a result, the endpoint’s numerical finding and its precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry specifies a percentage endpoint and an exact Clopper-Pearson 95% confidence interval. In general, a percentage for a binary outcome is formed by classifying each included participant according to whether the outcome occurred, then describing the proportion in the outcome category of interest. For this endpoint, the category of interest is a plasma DMPA concentration below 0.1 ng/mL at Week 12. The registry record does not report the observed count or percentage, so neither can be restated.

What does the confidence interval express?

In general, a confidence interval describes the uncertainty in an estimate that arises from observing a sample rather than an entire target population. A 95% confidence interval gives a range of values compatible with the data under the interval’s statistical assumptions and procedure. Its width is informative about precision: a wider interval indicates less precision than a narrower interval. The actual limits are not reported in the registry record, so the precision of the Week 12 percentage cannot be judged from the posted result information.

The Clopper-Pearson procedure is an exact method for a binomial proportion. It is based on the number of participants in each outcome category and the analyzed sample size. The term exact refers to the interval construction rather than to a guarantee that the estimate is free of uncertainty or bias. As a general statistical matter, an exact interval can be conservative, meaning that its actual coverage may exceed its nominal coverage under some conditions. It does not address sources of uncertainty arising from missing measurements, selection into the analysis population, measurement error, or limitations in the study design.

Why does the threshold matter?

The endpoint reduces a measured concentration to a binary classification relative to 0.1 ng/mL. This makes the result easy to interpret against the study’s stated pharmacokinetic threshold, but it also discards information about how far a concentration lies from that threshold. Two participants with different measured concentrations can fall into the same category, while small differences on opposite sides of the cutoff produce different classifications. This is a general feature of threshold-based analyses, not evidence about the particular participants in this study.

The registry description connects concentrations at or above the threshold with general suppression of ovulation. That statement explains why the threshold was of interest; it does not make the primary measure equivalent to ovulation. A pharmacokinetic concentration is a measure of drug exposure. An outcome that directly records ovulation would be a different endpoint. The registry record does not report the primary endpoint’s numerical value or a direct Week 12 ovulation result.

How should repeated concentration outcomes be understood?

The secondary outcomes include the percentage of participants with DMPA concentrations below 0.1 ng/mL at weeks 2, 4, 6, 8, and 10, and a cumulative percentage with concentrations below the threshold. In general, repeated measurements describe how a quantity changes or how often a threshold is crossed across follow-up. Measurements from the same participant are related, so they should not automatically be treated as independent observations. The registry record does not describe a model for repeated measurements or report numerical results for these secondary outcomes.

The listed pharmacokinetic measures summarize different aspects of drug exposure. In general, AUC represents exposure integrated over time; Cmin and Cmax refer to minimum and maximum concentrations in the relevant measurement interval; half-life describes the time course of decline in concentration; and apparent clearance represents clearance as estimated in relation to bioavailability. The registry lists these outcomes, but does not report their estimates or the detailed methods used to derive them.

What can planning calculations tell readers?

In general, sample-size calculations are planning tools that describe how many participants might be needed under specified assumptions. The registry’s planning-illustration description refers to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of an observed effect. It also specifies that time-to-event illustrations use total events, while other illustrations use participants per arm. These are planning assumptions, not a description of the actual single-group trial design. Any such planning values are not observed power and do not establish the precision or outcome of this study. The registry record does not report the trial’s own sample-size justification.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Arm A: Depot Medroxyprogesterone Acetate")
n      <- c(42)
events <- c(5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Arm A: Depot Medroxyprogesterone Acetate  42  5  11.9  4.0  25.6  5.2  25.0  5.3  25.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and a set of secondary outcomes. The primary endpoint is the percentage with a DMPA concentration below 0.1 ng/mL at Week 12. Secondary outcomes include percentages at earlier time points, a cumulative percentage below the threshold, pharmacokinetic measures, and Grade 3 or higher signs, symptoms, or laboratory abnormalities. The registry record does not report a multiplicity adjustment or explain how the interpretation of multiple secondary outcomes was controlled. Without such information, secondary findings, if reported elsewhere, would need to be interpreted with care because examining multiple outcomes can increase the chance of at least one apparently unusual result by chance. This is a general statistical concern, not a claim about any unreported result in this study.

The stated primary analysis excluded participants who did not have DMPA concentrations at weeks 10 and 12. The registry record does not report the number of participants affected, whether missingness arose for similar reasons across participants, or whether any alternative analysis was conducted. It also does not describe imputation or sensitivity analyses. Missing measurements can matter because the analyzed group may differ from the enrolled group; the direction and extent of any effect cannot be determined without further information.

The registry’s stated exclusion rule is the only reported detail about the primary analysis population. The record does not describe other eligibility restrictions for the analysis, deviations from the planned treatment, or the handling of participants with incomplete follow-up beyond that rule. The enrollment count of 62 should not therefore be assumed to equal the denominator used for the primary endpoint. The actual analysis denominator is not reported in the registry record.

The record does not report a complete statistical analysis plan, including planned handling of multiplicity or missing data. Such details should not be inferred from the endpoint description alone.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bicytopenia (1.6%).

The registry lists one study group with 62 participants at risk for the serious adverse event summary. It reports 1 participant affected by a serious adverse event, 6 participants affected by other adverse events, and 1 death. These are descriptive counts for the study group; the registry record does not provide a comparator group against which to assess relative risk.

The listed serious-event term is bicytopenia, reported as 1.6%. The registry does not provide further event-level detail in the information summarized, so that term and percentage should not be expanded into assumptions about timing, duration, severity beyond its listing, or relationship to a particular medicine. The count of participants affected by other adverse events is not accompanied by a list of their terms.

The death count is reported separately from the counts of participants affected by serious and other adverse events. The registry record does not state whether the death was considered related to study treatment or how it relates to the serious-event count. These figures therefore describe what the registry recorded, not a causal assessment. In a single-group study, they also cannot establish whether event frequency differs from what would have occurred with another regimen.

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

The study’s primary endpoint was designed to describe the proportion of analyzed participants whose DMPA concentration fell below 0.1 ng/mL at Week 12 while they were receiving DMPA with RIF and EFV. The endpoint is relevant to the study’s pharmacokinetic question because the registry description identifies the threshold in relation to general ovulation suppression. The percentage and its exact 95% confidence interval are not reported in the registry record, however. No numerical conclusion about the primary endpoint’s frequency or precision can be drawn from that record.

Even if the concentration percentage were available, it would answer a narrower question than whether DMPA prevented pregnancy or whether ovulation occurred. Concentration is a pharmacokinetic measure, while ovulation and pregnancy are clinical outcomes. The registry description explains the biological reason for examining the threshold, but does not make the concentration endpoint interchangeable with those outcomes.

The single-group design can describe observations among participants who received the study regimen. It does not provide a randomized comparison with another DMPA schedule or a group receiving different medicines. Consequently, it cannot by itself establish that any observed concentration pattern was caused by RIF, EFV, or their combination, nor can it directly determine which dosing frequency is best. The registry record also does not report a comparative analysis or an outcome estimate that would answer those broader questions.

The analysis excluded participants without concentrations at weeks 10 and 12, and the number excluded is not reported. The enrolled count of 62 therefore does not establish the denominator for the primary result. The record also does not report numerical results for the listed secondary pharmacokinetic outcomes. These gaps limit assessment of both the size and the reliability of the findings from the registry record alone.

Safety counts describe events observed in the study group, but do not establish causation or comparative safety. The registry’s reported counts should be read as descriptive rather than as evidence for or against a treatment effect.

14. Why This Trial Matters Statistically

This trial raises a statistical issue common to pharmacokinetic research: a measured drug concentration may be used as a marker related to a clinical process, but it is not identical to that clinical process. The Week 12 endpoint classifies concentrations relative to 0.1 ng/mL, a threshold the registry associates with general suppression of ovulation. Clear distinctions between the biomarker, the threshold, and a direct clinical outcome are essential when interpreting what an endpoint can establish.

The study also illustrates the tradeoff in a single-group design. Repeated concentration measurements can describe the time course in the participants studied, and the listed pharmacokinetic measures can characterize exposure in different ways. But without a control group, differences cannot be attributed confidently to one medicine or compared directly with an alternative schedule. The study’s open-label, non-randomized design makes the distinction between description and causal comparison especially important.

Precision is another key part of interpretation. The registry specifies an exact confidence interval for the primary percentage, but does not report the percentage or interval limits. Without them, readers cannot judge whether the estimate is precise or uncertain. The analysis-population rule also matters: participants without concentrations at weeks 10 and 12 were excluded, while the number excluded and their characteristics are not reported.

Finally, a list of several secondary outcomes creates questions about multiplicity and analysis choices. The registry does not report a multiplicity adjustment or a complete statistical analysis plan. These are not reasons to assume that a particular analysis was invalid; they identify information needed to assess how strongly any multiple findings should be interpreted. The record is most informative about the question, design, endpoint definition, and stated analysis method, and less informative about the numerical results and their uncertainty.

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 the primary endpoint estimate, the exact confidence interval limits, or the number of participants included in that analysis. Since participants without DMPA concentrations at weeks 10 and 12 were excluded, the enrollment count of 62 cannot be treated as the primary analysis denominator without further information. The number and reasons for exclusions are not reported in the registry record.

The single-group, non-randomized, open-label design has no like-for-like control comparison. It can describe the observations within the group, but cannot isolate the contribution of each co-administered medicine or support a randomized comparison of DMPA schedules. This is particularly relevant because DMPA was given with both RIF and EFV, while the study population was described as also taking INH.

The primary measure is a concentration threshold at Week 12. The registry links the threshold to general ovulation suppression, but the primary endpoint is not a direct measure of ovulation or pregnancy. The record does not report a Week 12 ovulation result alongside the concentration endpoint. Nor does it report numerical results for the listed secondary pharmacokinetic outcomes.

Further limitations in assessing the evidence arise from unreported methods. The registry does not report the trial’s sample-size justification, a complete statistical analysis plan, multiplicity handling, or additional missing-data analyses. The safety summary provides group counts and one listed serious-event term, but does not establish causality or comparative risk. These limitations concern what can be evaluated from the registry record; they do not establish what occurred in unreported analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: PK Study of Rifampicin Interactions With DMPA and Efavirenz in TB — NCT02412436.
• Registry record last updated 2019-07-01; status last verified 2019-06.
• Results first posted 2018-09-25.
• 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

NCT02412436 is a completed Phase 2, open-label, non-randomized, single-group study with 62 enrolled participants. It examined pharmacokinetic interactions involving DMPA, RIF, and EFV in women co-infected with HIV and tuberculosis. Participants received a single 150 mg intramuscular DMPA dose at week 0 while co-administered RIF and EFV.

The primary endpoint was the percentage of participants with a plasma DMPA concentration below 0.1 ng/mL at Week 12, with an exact Clopper-Pearson 95% confidence interval specified. Participants without concentrations at weeks 10 and 12 were excluded from the primary analysis. The endpoint estimate, confidence interval, and analysis denominator are not reported in the registry record. Safety listings include 1 participant with a serious adverse event, 6 with other adverse events, and 1 death; bicytopenia is listed at 1.6% as a serious event term.