Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy (NCT03965923), a randomized phase 3 study. The primary outcome is Number of Participants With a Composite Safety Endpoint Adverse Event (AE).

2. Clinical Question

3. Trial Design

This was a Phase 3b, randomized, open-label safety trial, with no masking and a sequential model. The registry record lists HIV Infections as the condition and the National Institute of Allergy and Infectious Diseases (NIAID) as sponsor. The study is marked completed, with enrollment of 1104. Its start date is 2020-01-09 and its primary completion date is 2024-05-13.

Maternal participants were organized into three cohorts according to gestational age at entry. Cohort 1 covered 36 0/7 weeks - 37 6/7 weeks; Cohort 2 covered 30 0/7 weeks - 35 6/7 weeks; and Cohort 3 covered 12 0/7 weeks - 29 6/7 weeks. Within each cohort, the registry lists mothers assigned to the DPV vaginal ring and mothers assigned to daily oral Truvada. The ring was used continuously and replaced approximately monthly, while Truvada was taken as one oral tablet daily. Both regimens continued until the pregnancy outcome, but no later than 41 6/7 weeks of gestation.

Infants were grouped according to their mothers’ cohort and assigned regimen. The primary endpoint was measured through the last study visit: approximately Week 12 to 36 for mothers, depending on cohort, and approximately Week 52 for infants. These differing follow-up windows are important context when reading counts across maternal and infant groups.

Although randomization is recorded, the registry record does not report the randomization method, allocation ratio, or a statistical analysis plan. The sequential cohorts and differences in group sizes mean that the posted arm counts should not be read as a single, simple head-to-head comparison of the two regimens across the entire study.

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.

Only the first 6 of 12 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All mothers who were randomized and enrolled are included. All enrolled infants are included.

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.

Only the first 6 of 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With a Composite Safety Endpoint Adverse Event (AE), measured over Measured through participant's last study visit. For mothers, this occurred at approximately Week 12 to 36, depending on participant's cohort, and for infants at approximately Week 52..

The primary endpoint counts participants who had at least one composite safety endpoint adverse event. Under the registry definition, this includes an adverse event classified as serious or an event graded 3 or higher under the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. A participant with more than one qualifying event still contributes once to this count, because the measure is the number of participants with at least one composite event.

The endpoint was used to summarize a broad safety outcome for both mothers and infants. Combining serious events with Grade 3 or higher events captures outcomes selected by severity, rather than counting every reported adverse event as part of the primary measure. The registry record specifies that mothers who were randomized and enrolled and all enrolled infants were included in the endpoint population. Follow-up ended at each participant’s last study visit, with different approximate visit timing for mothers and infants.

The counts are not a complete description of the type, timing, duration, or number of all adverse events. Nor does the composite count by itself indicate which component drove a group’s result. Serious adverse events and other adverse events are listed separately in the safety reporting; the composite endpoint also includes qualifying Grade 3 or higher events that need not be serious. The posted results should therefore be read as participant counts for the stated composite, alongside the separate safety summaries, rather than as a measure of all possible safety dimensions.

7. Results Posted in the Registry

• Cohort 1 Mothers: Truvada Tablet: 12.2% (6/49) versus 2.0% (2/101) on control; risk difference 10.3 percentage points (95% CI 0.7 to 19.8), risk ratio 6.18 (1.29–29.53); unadjusted two-proportion z-test p = 0.009.
• Cohort 2 Mothers: Dapivirine (DPV) Vaginal Ring (VR): 15.1% (16/106) versus 2.0% (2/101) on control; risk difference 13.1 percentage points (95% CI 5.8 to 20.5), risk ratio 7.62 (1.80–32.32); unadjusted two-proportion z-test p = <0.001.
• Cohort 2 Mothers: Truvada Tablet: 9.8% (5/51) versus 2.0% (2/101) on control; risk difference 7.8 percentage points (95% CI -0.8 to 16.4), risk ratio 4.95 (0.99–24.64); unadjusted two-proportion z-test p = 0.030.
• Cohort 3 Mothers: Dapivirine (DPV) Vaginal Ring (VR): 11.9% (24/202) versus 2.0% (2/101) on control; risk difference 9.9 percentage points (95% CI 4.7 to 15.1), risk ratio 6.00 (1.45–24.89); unadjusted two-proportion z-test p = 0.004.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Infant Drug Levels: Number of Infants With Detectable Infant Blood Tenofovir Diphosphate (TFV-DP)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Cohort 2 Infants: Truvada Tablet: 70.0% (35/50) versus 68.2% (30/44) on control; risk difference 1.8 percentage points (95% CI -16.9 to 20.5), risk ratio 1.03 (0.78–1.35); unadjusted two-proportion z-test p = 0.849.
  • Cohort 3 Infants: Truvada Tablet: 69.8% (30/43) versus 68.2% (30/44) on control; risk difference 1.6 percentage points (95% CI -17.9 to 21.0), risk ratio 1.02 (0.77–1.36); unadjusted two-proportion z-test p = 0.873.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort 2 Infants: Truvada Tablet and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort 3 Infants: Truvada Tablet and the control. The interval gives the range of effects that remain compatible with the data.

Infant Drug Levels: Number of Infants With Detectable Blood Emtricitabine Triphosphate (FTC-TP)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Cohort 2 Infants: Truvada Tablet: 12.0% (6/50) versus 15.9% (7/44) on control; risk difference -3.9 percentage points (95% CI -18.0 to 10.2), risk ratio 0.75 (0.27–2.08); unadjusted two-proportion z-test p = 0.584.
  • Cohort 3 Infants: Truvada Tablet: 2.3% (1/43) versus 15.9% (7/44) on control; risk difference -13.6 percentage points (95% CI -25.3 to -1.9), risk ratio 0.15 (0.02–1.14); unadjusted two-proportion z-test p = 0.028.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort 2 Infants: Truvada Tablet and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Cohort 3 Infants: Truvada Tablet than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Infant Drug Levels: Number of Infants With Detectable Plasma DPV

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Cohort 2 Infants: Dapivirine (DPV) Vaginal Ring (VR): 32.0% (31/97) versus 23.4% (22/94) on control; risk difference 8.6 percentage points (95% CI -4.1 to 21.2), risk ratio 1.37 (0.86–2.18); unadjusted two-proportion z-test p = 0.187.
  • Cohort 3 Infants: Dapivirine (DPV) Vaginal Ring (VR): 16.5% (30/182) versus 23.4% (22/94) on control; risk difference -6.9 percentage points (95% CI -17.0 to 3.2), risk ratio 0.70 (0.43–1.15); unadjusted two-proportion z-test p = 0.163.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort 2 Infants: Dapivirine (DPV) Vaginal Ring (VR) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort 3 Infants: Dapivirine (DPV) Vaginal Ring (VR) and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists secondary outcomes concerning pregnancy complications, infant drug levels, maternal drug concentrations, and adherence. Three infant drug-level outcomes have posted group counts and recalculated comparisons: detectable infant blood TFV-DP, detectable blood FTC-TP, and detectable plasma DPV. The available results do not form a single, uniform pattern of contrasts across cohorts and measures. Several intervals are broad, and some span values on both sides of zero. For one FTC-TP comparison, the Cohort 3 contrast is -0.136, with an interval from -0.253 to -0.019 and an unadjusted p-value of 0.028; the registry record does not list a sponsor-reported analysis for this outcome.

These secondary outcomes address drug presence or exposure and are not interchangeable with the primary composite safety endpoint. Detectable drug levels do not by themselves establish a safety outcome, and they do not tell whether a participant experienced a serious or Grade 3 or higher event. Likewise, a composite adverse-event count does not determine whether infant drug levels were detectable. The measures provide different kinds of information and should be interpreted as complementary descriptions rather than as confirmation of one another.

The posted secondary findings are exploratory in the sense that the registry record does not report a multiplicity procedure, a hierarchy of hypotheses, or a prespecified statistical plan. When many outcomes and contrasts are examined, unadjusted p-values do not account for the number of opportunities to observe an apparently notable result. This raises the possibility of chance findings and reduces the weight appropriate for any isolated nominal result. The registry record also does not include reported analyses for the listed secondary measures, so the recalculated contrasts should not be treated as sponsor-confirmed inferential findings.

The overall secondary pattern therefore adds detail on drug-level detection, but it does not resolve the comparative interpretation of the primary safety counts. The conclusions remain constrained by cohort structure, reference-group choices, uncertainty, and the absence of a reported multiplicity and analysis plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Pregnancy Complications: Frequency of Pregnancy Complications
• Infant Drug Levels: Number of Infants With Detectable Infant Blood Tenofovir Diphosphate (TFV-DP)
• Infant Drug Levels: Number of Infants With Detectable Blood Emtricitabine Triphosphate (FTC-TP)
• Infant Drug Levels: Number of Infants With Detectable Plasma DPV
• Adherence: Maternal Blood TFV-DP Concentrations
• Adherence: Maternal Blood FTC-TP Concentrations
• Adherence: Maternal Plasma DPV Concentrations
• Adherence: Frequency of Missing Taking the Pills

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary count represent?

The endpoint is binary at the participant level: a participant either had at least one qualifying composite event or did not. The posted outcome is the count of participants with an event, alongside the group denominator. This is distinct from an event count, because multiple qualifying events in one participant do not increase the number of participants counted for this endpoint. The definition combines serious adverse events and adverse events graded 3 or higher; it does not include every reported event automatically.

What is a risk difference?

A risk difference expresses the difference between the proportion with an event in one group and the proportion in its reference group. It is an absolute contrast, on the event-proportion scale. A value above zero means the event proportion is higher in the compared group than in the reference group; a value below zero means it is lower. A risk difference is not a relative measure, and it should be interpreted only when the two groups and reference make sense for the question being asked.

For these results, the recalculated comparisons use Cohort 1 mothers assigned to DPV ring as the reference group. This is explicit in the posted comparison inputs: the reference count and denominator are 2 and 101. That reference is distinct from the infant groups, and it is also from a different gestational-age cohort than the Cohort 2 and Cohort 3 maternal groups. Thus, the numerical contrasts are not automatically estimates of the effect of one regimen versus the other among otherwise comparable randomized participants.

How should an interval be read?

A confidence interval describes uncertainty around an estimated contrast under the assumptions of the method used. A narrower interval indicates greater precision; a wider interval leaves a broader range of values compatible with the data and method. If an interval includes zero for a risk difference, values corresponding to no difference remain compatible with that interval. This does not prove equivalence or absence of an effect. Conversely, an interval that does not include zero does not remove concerns about whether the groups are comparable or whether the analysis answers the intended clinical question.

The registry record does not identify the confidence level, method used to form these intervals, or statistical model. The posted comparisons are described as unadjusted recalculations, and no reported primary analyses are listed in the registry record. It is therefore appropriate to explain the intervals as uncertainty summaries while avoiding assumptions about the exact inferential procedure.

What does a p-value add?

A p-value is a measure of how incompatible the observed data are with a particular null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. Small event counts, interval width, and the choice of comparison all matter alongside a p-value. Here, unadjusted p-values accompany recalculated contrasts, but the registry record does not report a prespecified testing strategy or describe adjustments for multiple comparisons.

There is also a visible difference between some interval and p-value readings. The Cohort 2 maternal Truvada contrast has an interval from -0.008 to 0.164 and an unadjusted p-value of 0.03. The registry record does not specify the methods or explain the difference. Those two summaries should be reported as posted, not silently treated as interchangeable or reconciled by assuming an undocumented analysis method.

Why does the cohort structure matter?

The trial is recorded as randomized, open label, and sequential, with arms organized within gestational-age cohorts. However, the registry record does not describe how randomization was implemented, whether each treatment contrast was intended to be analyzed within cohort, or whether any adjustment was used. The posted recalculated comparisons use one maternal group as the common reference, including for infant results. These features prevent a simple reading of every contrast as a randomized treatment comparison. Random allocation is relevant to design, but the reported comparison still needs a valid, well-defined reference group and an analysis aligned with the trial question.

Maternal and infant follow-up also differs. Maternal outcomes were followed through the last study visit, approximately Week 12 to 36 depending on cohort, whereas infant outcomes were followed through approximately Week 52. The registry record does not report a time-to-event analysis for the primary endpoint. The endpoint summaries are counts of participants with events, so differences in follow-up and opportunity to observe an event should remain part of the interpretation.

What does open-label mean for interpretation?

Open label means masking is listed as none. The registry record does not state how this affected event ascertainment or whether outcome adjudication was masked. A severe-event definition can make the outcome more structured, but it does not establish that reporting and classification were unaffected by knowledge of assignment. This is a general consideration for open-label safety research, not a claim that bias occurred in this trial.

Overall, the endpoint is a useful way to summarize participants with a severe or serious adverse event, but a meaningful treatment comparison requires more than a difference in counts. The analysis population, reference group, follow-up, definitions, and prespecified statistical plan are all relevant. Several of these analysis details are not reported in the registry record.

11. Confidence Intervals and Precision

The risk-difference intervals indicate substantial uncertainty for many of the recalculated comparisons. For example, the Cohort 1 maternal Truvada contrast is 0.103, with an interval from 0.007 to 0.198. The Cohort 2 maternal DPV ring contrast is 0.131, with an interval from 0.058 to 0.204. The Cohort 3 maternal DPV ring contrast is 0.099, with an interval from 0.047 to 0.151. These intervals give a range of estimates compatible with the data and calculation method, rather than a single exact value.

Other maternal intervals include zero: the Cohort 2 Truvada interval runs from -0.008 to 0.164, and the Cohort 3 Truvada interval runs from -0.019 to 0.143. For infant comparisons, the intervals are also often broad. As one example, the Cohort 2 infant DPV ring contrast is 0.272, with an interval from 0.180 to 0.363. These are numerical contrasts to the listed reference, which is a maternal group; their precision does not make them appropriate randomized infant comparisons.

Precision depends partly on the number of participants and events, and sparse event data can leave considerable uncertainty. The arm denominators and event counts vary across cohorts and maternal or infant populations. An interval that excludes zero describes the calculated contrast under its assumptions; it cannot correct a poorly matched reference or account for unreported design and analysis details. In addition, the registry record does not specify the interval method or confidence level. Thus, intervals are best read as a measure of uncertainty around the displayed recalculation, not as a complete assessment of the reliability or clinical meaning of a comparison.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures express participants per arm for 80% power and participants per arm for 90% power. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect used for planning is a stated fraction of the observed effect. The displayed planning contrasts are binary outcomes, so their figures are participants per arm rather than total events.

The 80% power column gives the approximate number of participants needed in each arm, under those assumptions, to detect the specified effect with 80% power. The 90% power column gives the corresponding number for 90% power. In plain terms, power describes the chance that a study would detect an effect of the chosen size if that effect were present and the planning assumptions held. The registry record does not report that these were the assumptions used to design the actual trial; the original design assumptions are not reported in the registry record.

The rows planning for 100%, 75%, or 50% of the observed effect illustrate how sample-size needs change when the effect targeted for detection is smaller. Smaller effects generally require more participants to distinguish them from random variation under the same planning assumptions. For example, the Cohort 1 maternal comparison lists 98 participants per arm for 80% power and 130 for 90% power when using 100% of the observed effect; the figures rise to 145 and 193 when planning for 75% of that effect, and to 258 and 345 when planning for 50%.

These are planning illustrations based on observed estimates, not a record of the trial’s original sample-size calculation. They are not observed power: they do not describe the probability that the completed trial detected its true effect. They should not be used to infer that a result is reliable or unreliable solely from whether the completed group sizes match an illustrative figure.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.020; treatment proportion p₁ = 0.122; average p̄ = 0.071.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3635 = 0.7124.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3562 = 0.2998.
4. n = (0.7124 + 0.2998)² / (0.1026)² = 97.2, rounded up to 98 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.0198019801980198                          # control proportion
p1 <- 0.122448979591837                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3965923)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 98 (80% power), 130 (90% power)
 75% of observed effect: n per arm = 145 (80% power), 193 (90% power)
 50% of observed effect: n per arm = 258 (80% power), 345 (90% power)
power.prop.test: 97.2 
Simulated power at n = 98 per arm: 0.844 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a multiplicity adjustment, or a hierarchy specifying which outcomes and comparisons were primary for formal hypothesis testing. The trial lists a primary composite safety endpoint and multiple secondary outcomes, including several infant drug-level measures and maternal adherence measures. The posted comparisons also include multiple cohort and treatment-group contrasts. When many tests are considered, unadjusted p-values do not account for the chance of obtaining at least one small p-value through repeated testing. The listed p-values should therefore be treated as individual, unadjusted summaries rather than as multiplicity-controlled evidence.

Missing-data methods are not reported in the registry record. The primary endpoint population is described: all randomized and enrolled mothers and all enrolled infants are included. That statement identifies the intended population but does not explain how incomplete visits, missing endpoint assessments, withdrawals, or unavailable records were handled. The record also does not describe imputation, censoring, sensitivity analyses, or reasons for missing outcome information. Without those details, the completeness of follow-up and the effect of missingness on the results cannot be assessed.

The registry record does not report a detailed analysis population for the secondary outcomes beyond the posted denominators. It also does not specify whether analyses followed randomized assignment, how protocol deviations were handled, or whether any adjusted models were planned. No sponsor-reported analyses are listed for the posted outcomes. These absences do not establish that the study team performed no analyses; they mean that the registry record does not report them.

For these reasons, interpretation should separate the recorded event counts from inferential claims. The raw counts remain descriptive information, while confidence intervals and p-values depend on analysis choices that are not fully documented in the registry record. Multiplicity, missing outcome information, and analysis-population definitions are important unresolved features for judging how broadly the recalculated contrasts can be generalized.

15. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bronchiolitis (5.9%), pneumonia (4.2%), dehydration (4.2%), gestational hypertension (4.1%), sepsis neonatal (3.0%).

The safety summaries separate serious adverse events from other adverse events and list deaths among infants. Serious-event counts vary across groups: for mothers, the reported counts range from 1 in Cohort 1 DPV ring to 11 in Cohort 3 DPV ring; for infants, they range from 3 in Cohort 3 Truvada to 30 in Cohort 3 DPV ring. These are counts, with the corresponding group denominators reported separately. They should not be interpreted as rates without considering each denominator.

Other adverse events were reported in every group, with counts from 29 in Cohort 1 mothers assigned Truvada to 176 in Cohort 3 infants assigned DPV ring. The safety summary lists infant deaths as 1 in Cohort 1 Truvada, 4 in Cohort 2 DPV ring, and 4 in Cohort 3 DPV ring; the other listed groups have 0 deaths. These counts do not establish cause or relationship to treatment, which are not reported in these summaries.

The most frequently listed serious-event terms include bronchiolitis at 5.9%, pneumonia at 4.2%, dehydration at 4.2%, gestational hypertension at 4.1%, sepsis neonatal at 3.0%, and microcytic anaemia at 2.1%. Serious adverse-event counts are not identical to the primary composite endpoint, which also includes Grade 3 or higher events that are not serious.

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

The registry results describe a safety-focused trial of DPV vaginal ring and daily oral Truvada use among HIV-uninfected pregnant women and their infants. They document the number of participants with at least one composite safety endpoint event in each listed group, the associated group sizes, and separate adverse-event and infant drug-level summaries. Those observations are useful for understanding what was recorded during the study’s follow-up.

The results do not, by themselves, establish that either regimen is safer or less safe than the other. The registry labels the study randomized, but the listed comparisons use a common Cohort 1 maternal DPV ring reference, including for infant outcomes. The registry record does not report a prespecified comparative analysis, the randomization procedure, or how treatment contrasts were intended to be made. The sequential gestational-age cohorts and different follow-up periods also matter. In particular, a numerical contrast involving an infant group and a maternal reference is not a direct randomized comparison of infant outcomes.

The primary endpoint is a composite count, not a complete accounting of every safety aspect. It does not describe the specific event mix for each participant, the timing of events, or whether any event was related to assigned treatment. The serious-event summaries include group counts and selected terms, but they do not establish causality. The secondary drug-level measures assess detectable compounds at the 2-week post pregnancy outcome visit; they do not show that a medication prevented HIV infection or establish a safety effect.

Intervals and unadjusted p-values help describe statistical uncertainty, but they do not correct limitations in comparison structure or missing analysis details. A result that appears statistically notable should not be treated as decisive when multiplicity, missing-data handling, and the planned analysis are not reported. Likewise, a wide interval does not prove that groups are equivalent.

The registry record supports a careful account of observed safety outcomes and their uncertainty. It does not provide a basis for medical advice, a claim of treatment efficacy, or a definitive causal conclusion about comparative safety.

17. Why This Trial Matters Statistically

This trial is statistically instructive because it places randomized treatment groups within sequential cohorts defined by gestational age, then reports maternal and infant safety outcomes separately. A reader must distinguish the study’s randomized designation from the validity of each particular contrast. Randomization can support causal comparisons when the analyzed groups, outcome, and analysis correspond to the allocation. A recalculated comparison against a shared reference from a different population does not automatically inherit that interpretation.

The trial also illustrates why event counts, denominators, and follow-up windows should be read together. Maternal outcomes were measured through the last study visit, approximately Week 12 to 36 depending on cohort, and infant follow-up extended to approximately Week 52. Counts across those groups therefore summarize different populations and observation windows. Raw counts alone can be misleading when group sizes differ.

A broad composite endpoint can be useful for summarizing serious or severe events, but it combines categories that are not identical. The separate safety summaries help describe serious events and other events, yet do not replace a clear analysis plan. The absence of a reported multiplicity strategy and the presence of multiple outcomes also show why isolated unadjusted p-values deserve restrained interpretation.

Finally, the record distinguishes trial-design information from post hoc planning illustrations. The sample-size figures use observed effects under stated assumptions; they do not document the original design justification and do not represent observed power. Keeping those uses separate prevents a retrospective calculation from being mistaken for the trial’s protocol rationale. Together, these issues make the record a useful case for interpreting safety data with attention to estimands, comparators, precision, and reporting transparency.

18. 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 specific to this record constrain interpretation. The listed treatment groups are separated by maternal gestational-age cohort, and the model is described as sequential. The registry record does not report the allocation procedure, allocation ratio, or a planned within-cohort comparative analysis. Although the study is recorded as randomized, the recalculated contrasts use Cohort 1 mothers assigned to DPV ring as the reference across comparisons. That common reference is not an infant comparator and does not provide a clean direct treatment contrast for all groups.

Group sizes vary, and maternal and infant outcomes have different follow-up windows. The registry reports counts at the last study visit but does not report a time-to-event analysis or explain whether differences in follow-up opportunity were considered. The record also does not report how missing endpoint assessments, withdrawals, or incomplete follow-up were handled, nor does it detail the analysis populations beyond the primary endpoint population description.

The primary endpoint combines serious adverse events and Grade 3 or higher adverse events. The record does not report component-specific primary analyses, event timing, or treatment relatedness for the listed counts. The available comparison outputs are unadjusted recalculations, while no sponsor-reported analyses are listed. The interval method and confidence level are not reported, and at least one maternal contrast has a p-value and interval whose implications differ without an explanation in the registry record.

Finally, the registry record does not report the trial’s original sample-size justification, statistical analysis plan, or multiplicity approach. The secondary drug-level outcomes include only a subset of the outcomes described in the record, and their unadjusted comparisons should be interpreted cautiously. These gaps limit causal and inferential conclusions even though the event counts themselves are clearly reported.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy — NCT03965923.
• Registry record last updated 2025-08-12; status last verified 2025-05.
• Results first posted 2025-08-12.
• 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.

22. Record Summary

NCT03965923 is a completed Phase 3b randomized, open-label safety trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It enrolled 1104 participants and studied dapivirine vaginal ring and daily oral Truvada use in HIV-uninfected pregnant women and their infants. Maternal participants were assigned to sequential gestational-age cohorts, with infant groups organized by maternal cohort and regimen.

The primary outcome counted participants with at least one serious adverse event or Grade 3 or higher adverse event through the last study visit. The registry reports group-specific event counts, secondary infant drug-level results, and separate adverse-event summaries. Recalculated contrasts are unadjusted and use a Cohort 1 maternal group as a common reference; the registry record does not report sponsor analyses, a statistical analysis plan, or the original sample-size assumptions.