Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (NCT03239483), a randomized phase 1 study. The primary outcome is Frequency of Grade 2 or Higher Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, placebo-controlled, Phase 1 study with a parallel-group model and quadruple masking recorded in the registry. The intervention was dapivirine gel at 0.05%, administered rectally; the comparator was placebo gel. Both arm descriptions specify a single dose followed by 7 daily doses administered under direct observation in the clinic.

The registry lists enrollment of 28 and a completed status. The recorded study start was 2017-10-26, and primary completion was 2018-09-20. The record identifies the National Institute of Allergy and Infectious Diseases (NIAID) as sponsor and lists HIV Infections as the condition. Its stated purpose was to evaluate safety and pharmacokinetics in HIV-1 seronegative adults.

The primary outcome was the frequency of Grade 2 or higher adverse events. The registry defines the outcome population as enrolled participants who received at least one dose of study product, with follow-up from product initiation to study termination at approximately Day 40. The primary outcome counts are reported for 18 participants in the dapivirine arm and 9 in the placebo arm. The registry does not explain how these arm counts relate to the overall enrollment figure.

Acceptability outcomes were also listed, covering ease of use and comfort. The record lists 7 outcome measures and 3 analyses, but the information discussed for the primary safety comparison does not give results for the acceptability outcomes or explain how those analyses were selected. The registry record does not report a detailed statistical analysis plan or a sample-size justification.

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: enrolled participants receiving at least one dose of study product

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 Frequency of Grade 2 or Higher Adverse Events (AEs), measured over Measured after the participant has started study product until the participant's study termination at approximately Day 40.

The primary endpoint counts participants with one or more Grade 2 or higher adverse events. The registry describes severity using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, and/or the listed genital and rectal addenda. The assessment period begins after a participant starts study product and ends at study termination, approximately Day 40.

This endpoint is a participant count, not a count of all events. A participant with more than one qualifying event would still contribute as a participant with the outcome under the stated measure. The registry does not provide event-level detail for the primary outcome, so the number, timing, duration, or nature of qualifying events cannot be inferred from these counts.

Using a severity threshold focuses the outcome on events classified as at least Grade 2 under the specified grading framework. Such a measure can help describe short-term safety experience in an early-phase study. It does not, by itself, describe every aspect of safety, establish the cause of an event, or quantify the severity distribution above the threshold. The registry does not report a separate primary-outcome confidence interval or adjusted effect estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a Fisher exact test for the primary two-arm comparison. This method is used for categorical outcomes, such as whether a participant did or did not meet an event definition. In general, Fisher’s exact test evaluates how compatible the observed allocation of outcome counts across groups is with a null hypothesis of no association between group and outcome. It is commonly suitable when the data are counts and group sizes are limited, because its calculation uses the discrete distribution of possible tables rather than relying on a large-sample approximation.

The test’s p-value is 0.072. In general, a p-value is calculated under a specified null hypothesis and assumptions; it measures how often results at least as incompatible with that hypothesis as the observed results would occur under that model. It does not measure the size or clinical importance of a difference, and it is not the probability that the null is true. The record does not state the significance threshold or provide enough detail to describe any prespecified testing hierarchy.

The primary measure is a count of participants with an event, rather than a continuous measurement or a rate over person-time. The posted counts are 3 in the dapivirine arm and 5 in the placebo arm. A count-based comparison does not, by itself, show the event profile for each participant or how many total events occurred. The registry does not post event-level data for this outcome. No additional participant-level analysis can be reconstructed from the aggregate information described in the record.

A confidence interval would ordinarily help express the precision of an estimated treatment contrast. In general, it gives a range of values compatible with the data and the method used, subject to its assumptions. The registry reports no numerical interval or effect estimate for this primary comparison. Consequently, the p-value alone cannot show the plausible magnitude or direction of the difference with the same clarity as an estimate accompanied by an interval. The absence of a posted interval should not be interpreted as evidence that the estimate is precise or that the groups are equivalent.

The registry record marks further two-arm binary-endpoint values as missing or not estimable. Accordingly, no additional recalculated comparison or interval should be presented as if it were an available registry result. The reported Fisher exact analysis remains the numerical inferential result in the record. There is no discrepancy flag for this outcome, but the record does not supply a separate recalculated estimate to compare with the sponsor’s test.

Several general considerations apply to interpretation. Randomization is intended to support a fair comparison by assigning participants to groups through a chance process; it does not guarantee that every measured or unmeasured characteristic will be balanced, especially in small studies. Masking can reduce some forms of behavior or assessment bias, but the record’s masking label alone does not show whether masking was maintained for every participant or assessment. Neither feature replaces information about allocation procedures, adherence, missing outcomes, or the analysis population.

For binary outcomes, the observed counts depend on who was included and how the outcome was defined and assessed. The registry specifies a population that received at least one dose and a follow-up period through termination at approximately Day 40. It does not provide the number of participants with missing outcome data, the reasons for missingness, or a detailed rule for handling such data. These omissions limit assessment of whether the posted counts fully represent the intended analysis population.

Multiplicity is another general concern when many outcomes or analyses are examined. Testing multiple hypotheses can increase the chance of at least one apparently notable result if no adjustment or hierarchy is used. The record lists 7 outcome measures and 3 analyses, but does not report whether multiplicity adjustments, a hierarchical testing strategy, or prespecified distinctions between primary and exploratory analyses were used. No conclusion about adjustment should be inferred from the count of outcomes or analyses alone.

The study’s Phase 1 designation and stated safety and pharmacokinetic purpose are relevant to the role of the result. General early-phase interpretation emphasizes description and estimation as well as hypothesis testing. A single p-value does not summarize the full safety profile, and the primary threshold does not capture events below Grade 2 or other outcomes unless separately reported. The registry’s listed serious-event figures are a separate safety summary and should not be substituted for the primary Grade 2 or higher endpoint.

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("Dapivirine Gel", "Placebo Gel")
n      <- c(18, 9)
events <- c(3, 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  Dapivirine Gel  18  3  16.7  3.6  41.4  5.8  39.2  6.1  39.6
ARM  Placebo Gel  9  5  55.6  21.2  86.3  26.7  81.1  26.2  81.3

11. Analyses Reported by the Sponsor

The registry’s reported analysis is a Fisher exact test, with p = 0.072 for the comparison of Grade 2 or higher adverse-event counts between the dapivirine gel and placebo gel arms. No confidence interval or numerical between-group effect estimate is posted with that analysis. The registry also identifies values as missing or not estimable for a two-arm binary-endpoint comparison, so there is no separately reported recalculated estimate to set alongside the sponsor’s test.

The record does not flag a discrepancy between a sponsor analysis and a recalculation. The sponsor’s reported test is therefore the available inferential result, rather than one that can be replaced by a distinct recalculated result. The p-value should be read as evidence from the specified test, not as a measure of effect size or as proof of equivalence. Because the registry record does not give a confidence interval or an analysis description beyond the test name, the precision and complete analytic context of the sponsor’s comparison are not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures and 3 analyses, including the primary safety outcome and secondary acceptability outcomes for ease of use and comfort. The record does not report whether the primary outcome was tested within a prespecified hierarchy, whether any multiplicity adjustment was applied, or whether the other outcomes were treated as exploratory. Without that information, the p-value should not be interpreted as if the overall testing strategy were known.

In general, multiplicity matters when several hypotheses are tested because the chance of obtaining at least one apparently notable result can increase as the number of tests grows. An adjustment or a prespecified testing order can address this in some settings. The registry’s counts of outcomes and analyses do not establish whether either approach was used; the statistical plan is not reported in the registry record.

The primary outcome population is described as enrolled participants receiving at least one dose of study product. The registry lists enrollment of 28, and the primary outcome counts are reported for 18 participants in the dapivirine arm and 9 in the placebo arm. The record does not explain the relationship between enrollment and these outcome counts. It also does not report how many outcome observations, if any, were missing or how missing data were handled.

For a participant-count endpoint, missing outcome status can affect interpretation if the missingness differs by group or relates to the likelihood of an event. This is a general concern, not a claim that missing data occurred in this study. The record does not report reasons for missingness, a missing-data sensitivity analysis, or a detailed analysis-population flow. It is therefore not possible to assess those issues from the registry record.

The record does not report a detailed statistical analysis plan, the handling of protocol deviations, or whether the primary analysis followed an intention-to-treat or another named principle. The stated outcome population provides some information about eligibility for the endpoint, but it does not answer all questions about inclusion and analysis. These omissions limit reconstruction of the inferential process and should temper any claim extending beyond the recorded outcome counts and test.

13. 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’s separate serious adverse-event summary reports no serious adverse events in either arm and no deaths in either arm. It records 18 participants at risk in the dapivirine group and 9 at risk in the placebo group for serious events. These are serious-event figures, distinct from the primary outcome of participants with Grade 2 or higher adverse events, which has counts of 3 and 5.

In general, a recorded count of zero means no events were reported for that category in the listed group during the recorded reporting context. It does not establish that the underlying risk is zero or rule out uncommon events. The registry does not provide serious-event terms, with no top serious-event terms listed. The record also does not provide a confidence interval for these serious-event counts or an inferential comparison.

These figures describe the safety information recorded for this study and should not be conflated with the broader primary endpoint. The registry’s serious-event summary and its Grade 2 or higher adverse-event outcome use different event categories. The figures do not establish causation, and the record does not report enough detail to characterize timing, duration, relatedness, or clinical course of individual events.

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

The result means that, during the specified follow-up period, the registry recorded 3 participants with Grade 2 or higher adverse events in the dapivirine gel group and 5 in the placebo gel group. The registry reports a Fisher exact test p-value of 0.072. These registry entries describe the recorded outcome and its reported statistical comparison; they do not by themselves establish a causal explanation for the counts.

The p-value is not a measure of how large the difference is, and it does not give the probability that the treatments are the same. The record posts no confidence interval or numerical effect estimate for the primary comparison. It is therefore not possible to use the reported test alone to judge the precision of a group difference or to establish that the groups are equivalent. Likewise, the fact that the p-value is not below a commonly used threshold does not prove there is no difference.

The outcome concerns participants meeting a specified severity threshold, not every adverse event or every aspect of safety. It does not summarize pharmacokinetics, despite the study’s stated purpose including pharmacokinetic evaluation. The registry record does not report results for the listed acceptability outcomes in the information. The separate serious-event summary reports no serious adverse events and no deaths in either arm, but those categories are not interchangeable with Grade 2 or higher events.

These results apply to the study population, regimen, and assessment period recorded: HIV-1 seronegative adults receiving the specified rectal gel schedule, with follow-up through study termination at approximately Day 40. They do not establish what would happen under different schedules, in other populations, or over longer follow-up. The record does not report a detailed statistical plan, missing-data handling, or a sample-size justification. Accordingly, the findings should be interpreted as a limited short-term registry comparison, not as a complete account of comparative safety.

15. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between reporting event counts and estimating a group contrast. The registry gives counts of participants with Grade 2 or higher adverse events and a Fisher exact test p-value, but does not post a confidence interval or a numerical effect estimate. A test result alone cannot convey the range of plausible differences or how precisely the comparison is estimated.

The study is randomized, placebo-controlled, and masked, features that support a structured comparison. At the same time, the registry’s primary outcome counts do not match the listed enrollment figure, and the record does not explain that relationship. The analysis population is described as participants who received at least one dose, but the registry does not report a full analysis-population flow or missing-data handling. Those details matter because readers need to know who contributed to each comparison and how incomplete outcome information was treated.

The outcome also demonstrates why endpoint definitions matter. The primary measure counts participants who crossed a Grade 2 severity threshold over a defined period; it is not a tally of all events and is distinct from the serious adverse-event summary. The study lists pharmacokinetics and acceptability among its interests, but the primary safety comparison cannot stand in for those other domains.

Finally, the record lists multiple outcome measures and analyses without describing a multiplicity strategy or detailed statistical plan. This makes the context for interpreting the reported p-value less complete. Together, these features show why statistical reading should include endpoint definition, analysis population, uncertainty, and the scope of the registry record—not only the direction of observed counts or a single test result.

16. 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 offers limited context for the primary comparison. Although it lists enrollment of 28, the reported primary-outcome arm counts are 18 for dapivirine gel and 9 for placebo gel. The record does not explain the relationship between these figures. The endpoint population is described as participants who received at least one dose, but no participant flow is reported to clarify inclusion in the analysis.

The record does not report whether any primary outcome data were missing, why any data might be missing, or how missing observations were handled. It also does not report an intention-to-treat analysis or another named analysis principle. These are reporting gaps; they do not establish that missing data or protocol deviations occurred.

For the primary comparison, the registry reports a Fisher exact test p-value but no confidence interval or numerical effect estimate. The record indicates that additional two-arm binary-endpoint values are missing or not estimable. This restricts assessment of the magnitude and precision of the comparison. The sponsor’s reported test remains the available inferential result, and no discrepancy is flagged.

The registry does not report a detailed statistical analysis plan, a sample-size justification, an interim-analysis plan, or a multiplicity strategy. It lists 7 outcome measures and 3 analyses, but does not explain how testing across outcomes was organized. Results for the listed ease-of-use and comfort outcomes are not reported in the information.

Finally, the primary outcome covers participants with Grade 2 or higher adverse events through termination at approximately Day 40. It does not describe all event details or longer-term experience. The serious adverse-event summary is a separate measure. These limitations mean the registry result should be read narrowly as a recorded short-term endpoint comparison, not as a complete characterization of safety or pharmacokinetics.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults — NCT03239483.
• Registry record last updated 2021-10-19; status last verified 2019-10.
• Results first posted 2019-11-07.
• 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.

20. Record Summary

NCT03239483 is a completed, randomized, double-blind, placebo-controlled Phase 1 study of rectal dapivirine gel at 0.05% in HIV-1 seronegative adults. The registry records a parallel-group model and quadruple masking. The intervention and placebo schedules each consisted of a single dose followed by 7 daily doses administered under direct observation in the clinic.

The primary endpoint was the frequency of participants with Grade 2 or higher adverse events after starting study product through termination at approximately Day 40. The registry reports counts of 3 in the dapivirine arm and 5 in the placebo arm, with a Fisher exact test p-value of 0.072. No confidence interval or numerical effect estimate is posted for that comparison.

The record lists enrollment of 28, while the primary outcome arm counts are 18 and 9; the relationship is not reported in the registry record. The separate serious-event summary reports no serious adverse events and no deaths in either arm. The registry does not report detailed multiplicity or missing-data methods.