Assessment of a New "Boosting" Strategy for HIV Pre-exposure Prophylaxis in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assessment of a New "Boosting" Strategy for HIV Pre-exposure Prophylaxis in Healthy Volunteers (NCT03202511), a randomized early/phase 1 study. The primary outcome is Plasma TFV AUC0-INF GMR.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, crossover pharmacokinetic trial in healthy volunteers, classified as early phase 1. The registry lists 15 enrolled participants and Indiana University as the sponsor. The recorded study dates are 2017-06-23 for the start and 2018-07-02 for primary completion; the status is completed.

A crossover design compares treatment conditions within a study in which participants take part in more than one phase. This can make each participant a source of information for both conditions, but interpretation depends on design details such as treatment order, timing, and any period or carryover effects. The record identifies randomization and crossover but does not report the sequence allocation, phase interval, washout arrangements, or analyses of period and carryover effects.

The treatment phase consisted of TDF/FTC at 600/400 mg with 2 grams of probenecid on day 1. The control phase consisted of TDF/FTC at 600/400 mg on day 1 and 300/200 mg on days 2 and 3. The trial was unmasked, so participants and study personnel were not blinded to phase assignment.

The primary outcome concerned plasma tenofovir exposure. The stated sampling window was 0 to 72 hours after dosing, and the primary endpoint description names AUC0-INF. The registry also describes measuring tenofovir and emtricitabine in plasma, blood, and urine, and measuring intracellular tenofovir diphosphate and emtricitabine in peripheral blood mononuclear cells. It describes a secondary aim involving selected samples and urinary and serum markers related to renal and bone toxicity. Results for that secondary aim are not reported in the registry record.

The registry lists two outcome measures and two analyses. It does not report the full statistical analysis plan, the rationale for the enrollment target, or whether interim analyses were planned.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Primary result was performed for geometric mean ratio of treatment phase to control phase.

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 Plasma TFV AUC0-INF GMR, measured over The first 72 hours of each phase..

The primary endpoint is the geometric mean ratio of plasma tenofovir area under the concentration-time curve from zero to infinity (AUC0-INF), comparing the treatment phase with the control phase. The area under a concentration-time curve represents drug exposure over time: it combines measured concentrations across the observation period rather than describing concentration at only one moment. AUC0-INF refers to exposure estimated from the beginning of observation through an unbounded time horizon.

The registry states that pharmacokinetic samples were collected from 0 to 72 hours after dosing and that the primary timeframe was the first 72 hours of each phase. The record does not explain the method used to estimate AUC0-INF from those observations, including how any exposure after the sampling window was handled.

A geometric mean ratio expresses the relative exposure between phases on a multiplicative scale. A ratio of 1 would indicate equal geometric mean exposure; a ratio above 1 indicates a higher estimate in the treatment phase relative to control, while a ratio below 1 indicates a lower estimate. These are general interpretations of a ratio, not evidence about clinical outcomes. The registry reports a GMR of 1.61 and a 90% confidence interval of 1.47 to 1.77.

Pharmacokinetic exposure is used to characterize how the body encounters a drug under specified dosing conditions. It can inform comparisons between regimens, but it does not by itself establish prevention of infection, long-term safety, or clinical benefit. The registry's primary endpoint is a drug-exposure measure, not an HIV incidence endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a geometric mean ratio express?

General: Drug concentrations and exposure measures are often positive and can vary multiplicatively. For such data, an analysis may use logarithms, compare average values on the transformed scale, and then express the contrast as a ratio on the original scale. A geometric mean is constructed to represent a central value under this multiplicative approach. A geometric mean ratio compares the two phase-level geometric means. The registry reports a GMR of 1.61 for treatment relative to control, with a 90% confidence interval of 1.47 to 1.77.

The direction of the ratio depends on the stated order of comparison. In this trial, the registry explicitly defines the ratio as treatment phase to control phase. A ratio greater than 1 therefore indicates a larger estimated exposure in the treatment phase on this scale. This interpretation is specific to the comparison as defined; reversing the order would reverse the direction of the ratio.

What does the confidence interval convey?

General: A confidence interval gives an estimate together with a range reflecting sampling uncertainty under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, all else equal. It does not represent the range of individual participants' values, and it does not mean there is a specified probability that the true value falls inside the particular calculated interval. The registry gives a 90% confidence interval for the GMR, from 1.47 to 1.77. The method used to calculate that interval is not reported in the registry record.

A confidence interval's interpretation also depends on the model and data used to construct it. In a crossover trial, repeated measurements from the same participant are related. General statistical analyses need to account for this dependence rather than treating all phase measurements as if they came from unrelated participants. The registry identifies the crossover design but does not describe the analysis model or how within-participant dependence was handled.

Why is the endpoint an area under the curve?

General: A concentration at one sampling time gives a snapshot. An area under the concentration-time curve instead summarizes exposure across time, incorporating concentrations observed at multiple times. It is useful for pharmacokinetic comparisons because different concentration profiles can have similar values at one particular time yet differ in overall exposure. The endpoint named in the registry is AUC0-INF, while samples were collected from 0 to 72 hours. The record does not state how the unobserved portion after 72 hours was estimated, or how the AUC calculation was performed.

What does the crossover structure change?

General: A crossover design can compare conditions within participants, which may reduce the influence of stable differences between participants. However, observations across phases are not independent, and the design can be affected by period effects, treatment sequence, or carryover from one phase to another. A suitable analysis and adequate design details are important for interpreting the contrast. Randomization is reported, but the sequence, interval between phases, any washout, and assessment of period or carryover effects are not reported in the registry record.

The arm summaries list 14 participants for each phase, and the safety record lists different at-risk counts by phase. The registry does not explain the participant flow or missing observations. Without those details, it is not possible to establish from the record why the analysis and safety counts differ or how missing phase data were handled.

How should an equivalence label be understood?

General: Equivalence is a specific statistical claim that a treatment contrast is sufficiently close to a prespecified reference value, according to an acceptable margin. It is not established merely because an estimate is precise or because a statistical test is nonsignificant. The registry labels its analysis as equivalence and reports a ratio with a 90% confidence interval, but does not report an equivalence margin, its rationale, or the decision criteria. The label therefore cannot be independently evaluated from the registry record.

There is no reported p-value for the primary analysis, and the record does not identify a particular statistical test. A p-value, when reported, addresses compatibility with a specified null hypothesis under assumptions; it is not a measure of effect size, clinical importance, or the probability that a hypothesis is true. The GMR and its confidence interval provide the reported estimate and precision information, while important analysis specifications remain unavailable.

What can sample-size planning calculations establish?

General: A planning illustration based on an observed effect is not the same as the trial's original sample-size justification. Such an illustration depends on assumptions about the target effect, significance level, allocation, and statistical approximation. It cannot establish the power the completed trial actually had, and it should not be described as observed power. The registry record does not report the trial's sample-size justification or detailed design assumptions. Any planning illustration should therefore be interpreted as hypothetical rather than as evidence that the trial was prospectively designed to detect a particular effect.

10. Analyses Reported by the Sponsor

The registry reports the treatment-to-control GMR as 1.61, with a 90% confidence interval from 1.47 to 1.77, and labels the analysis as equivalence. It does not report a p-value or name the statistical method. The phase summaries are 8.75 for treatment and 8.27 for control, each with a 90% confidence interval, but the record does not explain their scale or how they relate numerically to the ratio.

No separate recalculated estimate is reported in the registry record, so there is no independent recalculation to compare with the registered GMR. The registry record does not flag a discrepancy. Consequently, there is no stated conflict between the registered analysis and a recalculated result; the posted GMR and interval remain the available comparative result.

The equivalence label should be read with the missing specifications in mind. An equivalence interpretation requires a prespecified margin and decision rule, neither of which is reported in the registry record. The reported ratio and interval describe the estimated exposure contrast and its precision, but the record does not provide enough detail to assess the equivalence criterion or reproduce the analysis.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and two analyses. The primary endpoint is plasma tenofovir AUC0-INF, while the study description also discusses a secondary aim assessing selected urinary and serum markers related to renal and bone toxicity. Results for that secondary aim are not reported in the registry record. The record does not identify all planned hypotheses, distinguish confirmatory from exploratory analyses, or describe a multiplicity adjustment.

Multiplicity arises when several outcomes, comparisons, or analyses are considered: the chance of at least one apparently unusual result can increase as the number of tests grows. General approaches include prespecifying a primary analysis, adjusting inference across tests, or clearly labeling secondary analyses as exploratory. The registry record does not report which approach, if any, was used. This limits interpretation of the wider analysis program, though it does not change the reported GMR itself.

The record also does not report the full analysis population definition, participant flow by phase, exclusions, or the handling of missing pharmacokinetic samples. The primary result lists 14 participants in each phase, while enrollment is 15. Safety counts differ by phase as well. The registry does not explain these counts or state whether all randomized participants were included in the primary analysis.

In a crossover study, missing measurements in one phase can affect the within-participant comparison and the amount of information available. General methods may use complete paired observations or other approaches, but the method used is not reported in the registry record. The record does not describe assumptions about missingness, imputation, sensitivity analyses, interim analyses, or a statistical analysis plan. These omissions make it difficult to evaluate how robust the primary estimate is to analysis choices or missing data.

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 safety record lists no serious adverse events in either phase: 0 of 14 participants at risk in the control phase and 0 of 15 at risk in the treatment phase. It also lists 0 deaths in each phase. These are the serious-event and death counts recorded for this study; they do not establish that the risk of serious events is absent.

For other adverse events, the record lists 2 of 14 participants affected in the control phase and 8 of 15 affected in the treatment phase. These are counts of participants affected, not a measure of event severity or a complete description of each event. The record does not provide the event terms, timing, duration, or participant-level detail for these other events. It also does not explain why the safety at-risk counts differ between phases.

Safety findings in a small, short pharmacokinetic trial have limited precision. The absence of recorded serious events in the observed participants does not rule out uncommon events or establish longer-term safety. The observed counts describe what the registry records for the study phases and should not be interpreted as a comparative safety conclusion or as a basis for treatment decisions.

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

The primary result is a pharmacokinetic comparison in healthy volunteers: plasma tenofovir AUC0-INF was summarized as a treatment-to-control geometric mean ratio of 1.61, with a 90% confidence interval of 1.47 to 1.77. The estimate points toward higher plasma exposure in the phase that combined TDF/FTC with probenecid than in the TDF/FTC control phase. The interval expresses statistical uncertainty around that estimate under the analysis used, whose details are not reported in the registry record.

This result does not directly measure HIV acquisition, prevention effectiveness, adherence, or health outcomes. It does not establish the effect of the regimen over long-term use or in people with characteristics different from the healthy volunteers enrolled. The trial's stated interest in a potential renal and bone toxicity advantage is not answered by the primary endpoint, and results for the described secondary markers are not reported in the registry record.

The registry labels the comparative analysis as equivalence, but an equivalence claim depends on an acceptable margin defined before interpreting the results. That margin and the analysis decision rule are not reported. The confidence interval alone cannot establish equivalence in the absence of that criterion.

The safety record reports zero serious adverse events in both phases and different counts of participants with other adverse events. Those observations do not prove that serious events cannot occur, nor do they characterize long-term risks. The study's enrollment, phase-specific analysis counts, and unreported analysis details also constrain how broadly or precisely the result can be interpreted.

Overall, the posted result describes a short-term drug-exposure contrast under the specific regimens and sampling conditions recorded. It is not a clinical recommendation, a conclusion about prevention efficacy, or a complete assessment of benefit and harm.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it uses a randomized crossover design to compare pharmacokinetic exposure across treatment phases. In general, crossover designs can use within-participant information, which may help distinguish treatment-related differences from stable participant-to-participant variation. At the same time, repeated observations require appropriate handling of their dependence, and interpretation can hinge on sequence, period, and carryover effects. The registry identifies the design but does not report the relevant design and analysis details.

The primary measure is a geometric mean ratio, a natural way to express a multiplicative exposure comparison. Reporting both an estimate and a confidence interval makes the direction and precision of the registered contrast more interpretable than a result presented only as a significance test. The GMR of 1.61 and its 90% confidence interval from 1.47 to 1.77 describe the exposure contrast recorded for this trial.

The analysis label also illustrates why statistical terminology needs its design context. Equivalence is not synonymous with similar-looking results: it requires an agreed margin and a rule for interpreting the interval relative to that margin. Those details are not reported in the registry record, so readers cannot assess the equivalence claim from the label alone.

Finally, this study separates pharmacokinetic questions from clinical outcomes. A measured exposure difference is informative about the regimen's drug levels under the study conditions, but it cannot by itself establish prevention outcomes or answer the proposed renal and bone questions. The registry's account of secondary aims without posted secondary results underscores the importance of distinguishing the primary estimate from outcomes that remain unreported.

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 leaves several trial-specific uncertainties. It reports 15 enrolled participants but lists 14 participants in each phase for the primary result. Safety at-risk counts are 14 in the control phase and 15 in the treatment phase. The record does not explain these differences, describe participant flow, or state how many participants contributed paired measurements.

Although the trial is described as randomized and crossover, the record does not report treatment sequence, the interval between phases, washout arrangements, or evaluation of period and carryover effects. These details matter because phase comparisons can be affected by the order and timing of exposures. The statistical method for the primary comparison is not specified, and the handling of within-participant correlation is not described.

The endpoint is named AUC0-INF, but samples are described as collected from 0 to 72 hours. The record does not explain how the portion of the exposure curve after the sampling window was estimated. It also does not clarify the scale of the phase summaries or provide the procedure used to calculate the confidence interval.

The equivalence analysis lacks a reported margin and decision rule. The record does not provide a sample-size justification, detailed statistical analysis plan, multiplicity approach, missing-data methods, or interim-analysis information. Results for the described secondary renal and bone markers are not reported in the registry record.

Finally, the trial enrolled healthy volunteers and reports a pharmacokinetic endpoint over the first 72 hours of each phase. The record does not support extrapolation to long-term treatment or clinical HIV prevention outcomes. The adverse-event details are limited, and no serious events in this study cannot resolve the possibility of uncommon or longer-term risks.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assessment of a New "Boosting" Strategy for HIV Pre-exposure Prophylaxis in Healthy Volunteers — NCT03202511.
• Registry record last updated 2021-05-07; status last verified 2021-04.
• Results first posted 2021-05-07.
• 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

NCT03202511 is a completed early phase 1 randomized, open-label crossover pharmacokinetic trial sponsored by Indiana University. The registry lists 15 enrolled healthy volunteers. The study compared a TDF/FTC control phase with a phase combining TDF/FTC and oral probenecid.

The primary endpoint was the treatment-to-control geometric mean ratio for plasma tenofovir AUC0-INF. The registry reports a GMR of 1.61 with a 90% confidence interval from 1.47 to 1.77 and labels the analysis as equivalence. No p-value or statistical method is reported. The record does not provide the equivalence margin or explain how AUC0-INF was estimated from samples collected through 72 hours.

The safety record reports no serious adverse events or deaths, with other adverse events affecting 2 participants in the control phase and 8 in the treatment phase. Results for the described secondary renal and bone markers are not reported in the registry record. Important details about missing data, participant counts, crossover procedures, and analysis populations are also not reported.