Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women (NCT02431273), a non-randomized early/phase 1 study. The primary outcome is Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs).

2. Clinical Question

The study asks whether intravaginal rings containing different antiretroviral combinations can be used safely and deliver their drugs in a sustained fashion in healthy women. Its stated focus includes safety and pharmacokinetics; the registry record also lists acceptability as a secondary outcome. The reported primary outcome concerns the number of participants with specific graded adverse events after use of each ring combination.

This question is descriptive rather than a randomized comparison of treatments. The study record gives counts of participants affected by serious and other adverse events for each combination. Those counts can describe what was recorded in these groups, but they cannot establish that one combination caused more or fewer events than another. The sequential design and lack of a control group also limit what can be concluded about safety relative to no ring or another intervention.

3. Trial Design

The registry describes an open-label, early-phase 1, nonrandomized, single-group study. Participants and study staff were not masked. The record lists enrollment as 10 and status as completed. The recorded study dates are start 2015-06 and primary completion 2016-12.

The planned sequence began with a TDF (single) IVR worn for 7 days. If that ring was determined safe, participants would be asked to replace it with a TDF-FTC (dual) IVR for 7 days. A follow-up visit was planned between removal of the single ring and replacement with the dual ring. If the dual ring was determined safe, participants would be asked to replace it with a TDF-FTC-MVC (triple) IVR for 7 days, with a follow-up visit between removal of the dual ring and replacement with the triple ring.

This conditional sequence matters for interpretation. The combinations were not assigned at random, and the record does not describe concurrent control arms. A comparison of counts across the three groups therefore is not a like-for-like randomized comparison. The registry does not report how the decision that a ring was safe was made, whether every participant progressed through each sequence, or why the at-risk count shown for each group is 6 while total enrollment is listed as 10.

The primary outcome is a participant count for graded adverse events over Days 0-21 following insertion of each IVR. The registry also lists acceptability as a secondary outcome and lists 7 outcome measures overall. It does not report participant-level measurements, pharmacokinetic summaries, or results for acceptability in the record represented by these registry entries. Statistical analysis methods and an analysis population are not reported in the registry record.

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.

TDF (Single IVR)

TDF-FTC (Dual IVR)

TDF-FTC-MVC (Triple IVR)

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: 6 subjects were screened, entered, and completed Period 1: TDF-IVR (Single IVR). The 6 subjects then completed Period 2: TDF-FTC (Dual IVR). 4 of the 6 subjects dropped out afterward. 2 of the 6 original subjects, plus 4 new subjects entered Period 3: TDF-FTC-MVC (Triple IVR). Here, baseline data of all subjects are presented.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs), measured over Days 0-21 following insertion of each IVR..

The primary outcome is the number of participants with specific graded adverse events in the single, dual, and triple antiretroviral IVRs. Its timeframe is Days 0-21 following insertion of each IVR. The registry says adverse events were recorded and that safety parameters were monitored for each combination.

Severity grading followed the Female Genital Grading Table for Use in Microbicide Studies for parameters covered by that table. Adverse events not included in it were graded using the Division of AIDS table identified in the record as Version 2.0, November 2014. The registry describes Grade 1 as mild, Grade 2 as moderate, Grade 3 as severe, and Grade 4 as potentially life-threatening.

Counting participants with events is useful for describing how many people in a group were affected, rather than only counting event occurrences. It does not show how many episodes each person experienced, when each event began, or whether an event was judged related to the ring unless those details are separately reported. Those details are not reported in the registry record. The posted safety figures distinguish serious adverse events from other adverse events, but do not provide a breakdown by grade or event term. The endpoint is a safety measure, not a direct measure of prevention effectiveness or pharmacokinetic exposure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry gives outcome definitions and descriptive event counts, but does not report inferential statistical analyses. The explanations below describe general statistical principles relevant to reading a small, nonrandomized safety study; they are not a claim that the study used any particular method.

What do participant counts describe?

In general, a count of participants with at least one event answers how many people in the analyzed group experienced an event under the outcome definition. This differs from an event count: one participant may experience more than one event, while a participant-level measure may count that person once for the specified category. The registry labels the primary measure as a number of participants. It does not report event-level records, recurrent-event summaries, or a breakdown of the participant counts by severity grade.

The number at risk is the group size associated with the reported safety measure. A count should be interpreted alongside that denominator and the outcome’s observation period. Here, the registry reports 6 at risk in each of the single, dual, and triple groups, and specifies Days 0-21 following insertion of each IVR. These details define the scope of the reported observations; they do not resolve how the groups were formed or why the at-risk count differs from the enrollment figure.

Why do design and allocation matter?

In general, random assignment helps make treatment groups comparable, on average, with respect to both measured and unmeasured characteristics. This study is listed as nonrandomized, without masking, and as a single-group model. Its sequence also depends on safety decisions: participants were to proceed from one ring combination to the next only if the preceding one was determined safe. These design features mean that group counts cannot be treated as results from a randomized head-to-head comparison.

Sequential exposure also affects how comparisons might be interpreted. A participant’s experience with a later combination occurs after the earlier combination in the described schedule, with follow-up between ring changes. General statistical reasoning cautions that sequence, time, prior exposure, and selection into later stages can complicate direct comparisons. The registry does not report an analysis accounting for these factors, or enough detail to determine how they were handled.

What would uncertainty estimates add?

In general, a confidence interval describes a range of values compatible with observed data under a specified statistical model and procedure. It helps communicate precision rather than presenting an estimate as exact. For a participant proportion, an interval would also need to account for the denominator and a method appropriate to the data. No confidence intervals or other uncertainty estimates are reported in the registry record, so the precision of the adverse-event summaries is not quantified by an inferential measure.

With small groups, estimates can be sensitive to the experience of individual participants. This is a general property of sparse data, not a separate result about the study. A descriptive count remains informative about what was observed, but by itself cannot establish how reliably that count represents outcomes in a wider population. The registry does not report a target precision or a sample-size justification.

How should event grading be understood?

In general, grading systems classify event severity according to defined criteria. The registry says genital safety parameters were graded using the Female Genital Grading Table for Use in Microbicide Studies, and other events were graded with the identified Division of AIDS grading table. The stated categories range from mild to potentially life-threatening. Applying a grading framework can make safety reporting more systematic, but interpretation still depends on the specific event, grade, timing, and attribution. Those details are not reported in the registry record’s adverse-event summary.

The posted counts separate serious events from other events; seriousness and severity grading are not interchangeable concepts in general. A serious-event category and a graded severity category can answer different questions. The record does not provide a cross-classification of seriousness and grade, so no such relationship should be inferred from the aggregate counts.

What analyses are not reported?

The registry lists no analyses in the information described for this study. It does not report a statistical test, model, adjustment set, missing-data approach, or analysis population. It also does not report interim analyses or a multiplicity procedure. These absences mean that inferential methods should not be attributed to the study based solely on the descriptive figures.

In general, methods for repeated observations may be relevant when the same participants contribute data across sequential treatment periods. Methods for sparse binary outcomes may be relevant when few events or participants are observed. Over-dispersion matters in general when a model assumes less variability than the data contain; accounting for it can prevent overly narrow uncertainty estimates. None of these approaches is identified as having been used in the registry record, and the available summaries are insufficient to select or reproduce a particular analysis.

10. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study evaluates several outcomes, comparisons, time points, or subgroups. In general, conducting many statistical tests can increase the chance of at least one apparently notable result when each test is considered separately. A prespecified analysis plan can clarify which outcomes and comparisons are primary and whether any adjustment is planned. The registry lists 7 outcome measures, but the registry entries do not report a multiplicity plan, a set of inferential comparisons, or adjusted results. The primary outcome is identified as the number of participants with specific graded adverse events; the record also lists acceptability as a secondary outcome.

Missing-data handling is not reported in the registry record. The adverse-event summaries provide at-risk counts, but they do not describe whether any observations were unavailable, how missing observations were defined, or how participants who did not proceed through the sequence were handled. The record does not state an analysis population, such as a population defined by enrollment, exposure, or completion. It would therefore be inappropriate to assume that all enrolled participants contributed to every outcome or that missingness was absent.

In general, missingness can affect interpretation when the likelihood of an observation being unavailable is related to a participant’s health, treatment exposure, or event experience. The direction and size of any effect depend on the circumstances and cannot be inferred from the counts alone. The registry also does not report a sensitivity analysis assessing alternative assumptions about unavailable data. These gaps limit evaluation of how complete and robust the safety summaries are.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

For serious adverse events, the registry reports 0 affected among 6 at risk in each of the single, dual, and triple IVR groups. Deaths are listed as 0 in each group. These are observed counts in the registry record, not proof that serious events or deaths cannot occur. The record lists no serious-event terms, and does not include further detail about event review or attribution.

For other adverse events, the registry reports 6 affected among 6 at risk with the single IVR, 6 among 6 with the dual IVR, and 4 among 6 with the triple IVR. The category is broad in the available summary. Event names, grades, recurrence, timing, duration, and relationship to the ring are not reported in the registry record.

The primary outcome timeframe is Days 0-21 following insertion of each IVR. These figures should be read within that defined observation period and the recorded at-risk groups. They do not establish a causal difference between the combinations, because the design was nonrandomized and sequential. The registry does not explain the relationship between the enrollment figure of 10 and the at-risk counts shown for each group. The counts are therefore useful as a compact description of reported safety observations, but should not be extended beyond their stated population, outcome categories, or timeframe.

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

The posted adverse-event results describe participant counts within three ring-combination groups. They report no serious adverse events and no deaths in the listed groups, alongside other adverse events affecting 6 participants in the single group, 6 in the dual group, and 4 in the triple group, with 6 at risk in each. This is a description of recorded observations, not a comparison establishing that one regimen is safer or less safe.

The findings do not show whether the reported other events were mild, moderate, severe, or potentially life-threatening. Although the registry describes grading procedures, it does not provide the event-by-grade results or event terms in this summary. The counts also do not explain whether events were considered related to a ring. More detail would be needed to understand the clinical character and timing of the safety observations.

The results do not establish efficacy for HIV prevention. The registry’s stated study aims include pharmacokinetics and sustained delivery, but pharmacokinetic results are not reported in the registry record. The listed secondary outcome of acceptability also has no results in the information. Thus, the safety counts alone cannot answer whether the rings delivered drug as intended, how long drug exposure persisted, or whether a ring reduced HIV risk.

General statistical interpretation also depends on design. This was an open-label, nonrandomized, single-group study with conditional progression through the combinations, rather than a randomized comparison with a control group. The figures should not be generalized to other populations or settings on the basis of this record alone. The record lists enrollment as 10, while each adverse-event group lists 6 at risk; it does not explain that difference. No inferential analyses, confidence intervals, or missing-data methods are reported.

The appropriate reading is narrow: the registry records the specified counts for the stated groups and observation period. The counts can inform a description of those observations, but they do not settle broader questions about comparative safety, pharmacokinetics, acceptability, or prevention effects.

13. Why This Trial Matters Statistically

This trial is statistically informative in part because its design makes the distinction between description and comparison especially important. A small, nonrandomized, open-label study can document whether events were recorded during exposure to different formulations, but counts across sequential groups do not have the same interpretation as estimates from a randomized head-to-head trial. The record’s conditional progression rule reinforces that the groups should not be treated as interchangeable controls.

The endpoint also illustrates why outcome definitions matter. The primary measure is the number of participants with specific graded adverse events, while the posted summary separates serious events from other events. Those summaries answer a limited question about how many participants were affected. They do not reveal event frequency per person, event severity distribution, timing, or attribution. A reader needs to distinguish what the measure captures from what the broader safety question might require.

The stated enrollment and at-risk counts also highlight the importance of accounting for analysis populations. The record lists enrollment as 10, while each reported group shows 6 at risk. Without an explanation of how participants contributed to each period or how incomplete follow-up was handled, it is not possible to reconstruct the analysis population. This is not a reason to discard the reported counts; it is a reason to keep conclusions tied to the groups and denominators actually reported.

Finally, the registry’s scope includes pharmacokinetics and acceptability, but the described results do not include those findings. Statistical interpretation cannot substitute for absent outcome data. The record is most useful when read as a limited safety description with important design and reporting constraints, rather than as a complete evaluation of all stated study aims.

14. Limitations

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

Several limitations are specific to this study record. The design is nonrandomized, open-label, and described as a single-group model. The treatment sequence is conditional on a preceding ring being determined safe, and the record does not state how that determination was made. Comparisons among the formulations may therefore reflect differences in sequence or progression as well as differences in the formulations themselves. There is no randomized control group for a like-for-like comparison.

The record lists enrollment as 10, while the adverse-event summaries show 6 at risk for each of the three combinations. It does not explain the relationship between those figures, whether each participant received every combination, or how participants who did not progress were handled. Missing-data rules and analysis populations are not reported. This limits the ability to understand the denominator and completeness of each outcome summary.

The available adverse-event results are aggregate counts. They do not specify the event terms, grades, timing, duration, recurrence, or relationship to the rings. The registry describes grading procedures but does not provide the corresponding grade-specific results. It also does not report confidence intervals, statistical tests, adjusted estimates, or other inferential analyses, so uncertainty is not quantified by a reported statistical method.

The study’s stated aims include pharmacokinetics, sustained delivery, and acceptability, but results for those outcomes are not reported in the registry record. The findings therefore cover only a portion of the study’s stated scope. Generalizability beyond the listed healthy-women population is not established by this record, and the small at-risk groups make the descriptive results particularly limited in scope.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women — NCT02431273.
• Registry record last updated 2019-07-02; status last verified 2019-06.
• Results first posted 2019-07-02.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes a completed, open-label, early-phase 1, nonrandomized study of TDF, TDF-FTC, and TDF-FTC-MVC intravaginal rings in healthy women. The planned sequence used each ring for 7 days, with progression conditional on the preceding ring being determined safe. Total enrollment is listed as 10.

The primary outcome is the number of participants with specific graded adverse events during Days 0-21 following insertion of each IVR. Each group lists 6 participants at risk. Serious adverse events and deaths are listed as 0 in each group; other adverse events are listed for 6 participants in the single group, 6 in the dual group, and 4 in the triple group.

The registry does not report inferential analyses, missing-data methods, or an analysis population. Pharmacokinetic and acceptability results are not reported in the registry record. The event counts are descriptive and do not establish comparative safety or prevention efficacy.