Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278LA, for Pre-Exposure Prophylaxis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278LA, for Pre-Exposure Prophylaxis (NCT02165202), a randomized phase 2 study. The primary outcome is Number of Participants Experiencing Any Grade 2 or Higher AEs During Injection Phase.

2. Clinical Question

3. Trial Design

The registry identifies NCT02165202 as a Phase II study of TMC278 LA for pre-exposure prophylaxis. It describes a multisite, double-blinded, randomized, two-arm trial with two:one allocation. The registry lists enrollment as 136 and status as completed. The recorded start is 2014-10, and the primary completion date is 2015-04-13. The registry's study-model field says “single group,” which does not align straightforwardly with the randomized, two-arm description and the separate rilpivirine and placebo arms. The record does not explain this inconsistency, so the design description should be read with that qualification.

The active regimen involved oral rilpivirine for four weeks followed by intramuscular TMC278 LA injections at eight-week intervals, on the listed schedule from Week 4 through Week 44. The comparator involved oral placebo for four weeks followed by saline injections on the corresponding schedule. The brief description frames the injections as being given once every eight weeks over a 40-week period. The registry lists PATH as the sponsor.

The primary endpoint follow-up extended to Week 52. Its analysis population consisted of participants who received at least one injection and were followed up to 52 weeks. The posted primary result includes 80 participants in the rilpivirine group and 42 in the placebo group. These endpoint denominators should not be mistaken for the overall enrollment figure: the record does not explain the difference between enrollment and the numbers included in this analysis. It also does not report recruitment flow, reasons for non-inclusion, adherence, or the number of participants completing each part of the regimen.

The registry record does not report the original sample-size justification, the details of sequence generation or allocation concealment, or the operational procedures used to preserve blinding. Those omissions limit how fully the design can be reconstructed from the record alone.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants will be randomized to either the active product regimen or the placebo arm at enrollment. Participants randomized to active and placebo product will first be prescribed oral TMC278 (rilpivirine) 25 mg capsule and oral placebo capsule, once daily for four weeks as an oral run-in and then will receive IM injections at week 4.

Oral Phase

Reasons for not completing this period:

Injection Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least one injection and were followed up to 52 weeks are included in this analysis.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: This template shows demographic characteristics of participants measured at Enrollment in the study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Experiencing Any Grade 2 or Higher AEs During Injection Phase, measured over Up to 52 weeks.

The primary endpoint counts participants who experienced any Grade 2 or higher clinical or laboratory adverse event during the injection phase. The assessment covers follow-up through Week 52, described as 48 weeks after the initial injection. A participant is counted for this outcome if at least one qualifying event occurred; the result is a count of participants with an event, not a count of all event episodes. The record does not give a breakdown of the primary outcome by event type or severity beyond the Grade 2-or-higher threshold.

This kind of endpoint is used to summarize whether participants experienced clinically or laboratorily important adverse events during the defined safety period. Counting participants rather than episodes avoids treating repeated events in one participant as if they came from different people. However, a single combined count does not show the nature, timing, duration, or recurrence of events. Nor does it convey whether events were judged related to treatment. The registry record does not report those details for the primary endpoint.

The stated analysis population includes participants who received at least one injection and were followed up to 52 weeks. That definition identifies who was intended to contribute to the outcome, but the record does not describe how incomplete follow-up or missing event information was handled. The posted counts are 59 among 80 in the rilpivirine group and 31 among 42 in the placebo group. These data address the specified adverse-event count; they do not alone answer broader questions about acceptability or every possible safety outcome.

7. Results Posted in the Registry

• Rilpivirine: 73.8% (59/80) versus 73.8% (31/42) on control; risk difference -0.1 percentage points (95% CI -16.5 to 16.4), risk ratio 1.00 (0.80–1.25); unadjusted two-proportion z-test p = 0.994.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry posts a binary participant-level primary outcome: whether a participant experienced at least one Grade 2 or higher adverse event during the defined follow-up. “Binary” means each participant contributes to the event or no-event classification for this endpoint. The posted arm results therefore give a number of participants with an event and an analysis denominator for each group. This is different from a count of all adverse-event episodes, because repeated events in one participant do not increase the number of participants counted as having the outcome.

What does the risk difference describe?

A risk difference compares the event proportions in two groups by subtracting one group's proportion from the other's. A value near zero indicates little separation in the observed proportions. A negative value, under the comparison direction used in the registry, indicates a lower observed proportion in the rilpivirine group than in the placebo group; a positive value indicates the reverse. The posted estimate is close to zero. Its confidence interval extends to both sides of zero, so the data are compatible with differences in either direction. The posted p-value for the unadjusted comparison is 0.994.

The risk difference is an absolute measure: it expresses the difference between group proportions rather than a relative multiplier. It is often useful for understanding how far apart the observed groups are on the outcome scale. It should be interpreted alongside its interval, since an estimate alone does not show its precision. The record also posts relative measures, including a risk ratio and an odds ratio. Those measures describe the comparison on different scales, and their intervals include the no-association value of one. They do not replace the primary risk-difference comparison.

Why does the confidence interval matter?

A confidence interval gives a range of values compatible with the data and the statistical procedure used to form it. In general, a narrower interval indicates greater precision, while a wider interval indicates greater uncertainty. For the risk difference in this trial, the interval spans zero and reaches into both directions. That means the result does not precisely identify the direction of a group difference. An interval crossing the null value is not proof that the groups are equal; it indicates that the data do not exclude the null value under the stated interval procedure.

Intervals are also useful for considering the magnitude of plausible effects, not just whether a null value lies within the interval. Here, the posted risk-difference interval is broad relative to an estimate close to zero. Without a clinical or scientific threshold specified in the registry record, the interval cannot be translated into a judgment about which differences would be important. No such threshold is reported.

What does the p-value tell the reader?

The unadjusted p-value is 0.994. In general, a p-value summarizes how unusual data at least as discrepant as those observed would be under a particular null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it is not a measure of the probability that the result will be replicated. The high p-value is consistent with the near-zero point estimate, but it cannot establish equivalence. The registry record does not report a detailed statistical analysis plan, the exact testing procedure, or whether other adjustments were used in analyses beyond the posted comparison.

“Unadjusted” describes the posted comparison as not adjusted for other variables. The record does not list covariates for an adjusted primary analysis. Consequently, the posted result should be read as an unadjusted comparison of the recorded groups. The record does not report whether an adjusted analysis was planned or performed elsewhere.

Why can event counts and analysis denominators differ?

The endpoint counts participants with an event among those included in its analysis. The denominator is the number included in that group's endpoint analysis. For the posted primary outcome, the rilpivirine group has 59 participants with an event among 80, and the placebo group has 31 among 42. The inclusion rule requires at least one injection and follow-up to 52 weeks. The registry record does not provide a participant-flow account or say how partial follow-up, missing assessments, or withdrawal was handled. The displayed denominators therefore describe the posted analysis, not necessarily every randomized participant.

In general, restricting an analysis to participants with a specified amount of follow-up can affect interpretation if inclusion is related to treatment group or event experience. That possibility is not evidence that such bias occurred in this trial. The record does not contain enough information to assess it. Details about missing-data assumptions and sensitivity analyses are not reported in the registry record.

What should be inferred from the statistical comparison?

The comparison quantifies the observed difference in the recorded endpoint and its uncertainty; it does not explain why any event occurred. Randomization is intended to make comparison groups comparable on average, but this record does not provide enough detail to evaluate all aspects of implementation. The trial is described as randomized and double-blinded, while its model field says single group. The mismatch is not resolved in the registry record. Statistical interpretation should remain anchored to the reported groups, endpoint, analysis population, and uncertainty rather than extending to unreported outcomes or causal mechanisms.

10. Confidence Intervals and Precision

The primary comparison is imprecise enough that the risk-difference confidence interval includes zero and extends in both directions. The point estimate is close to zero, but its interval allows for the possibility that the event proportion was lower in the rilpivirine group or lower in the placebo group. The posted p-value, 0.994, is consistent with little observed separation; it does not establish that the groups have the same underlying event risk.

A confidence interval is a range generated by a statistical method to express uncertainty about an estimated quantity. In general, narrower intervals indicate more precise estimates, while wider intervals leave more values plausible. For a risk difference, zero is the value corresponding to no difference. Because zero lies within the posted interval, the comparison does not rule out no difference. Because the interval also includes values away from zero in both directions, it does not tightly determine the magnitude or direction of a difference.

The interpretation depends on the endpoint, analysis denominators, and follow-up definition. The counts concern participants included after at least one injection and follow-up to 52 weeks, not necessarily everyone randomized. The registry record does not report a missing-data analysis or sensitivity analysis that would show how alternative assumptions affect precision. It also does not state a threshold for a clinically or scientifically important difference. Accordingly, the interval describes statistical uncertainty, but the record does not provide a decision margin for judging whether all values it contains would be practically negligible.

The relative-measure intervals also include their no-association value. They express uncertainty on scales different from the risk difference and do not remove the limitations of the endpoint analysis. Precision should therefore be judged from the interval as well as from the point estimate and p-value, without treating a non-significant comparison as proof of equivalence.

11. 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 are participants per arm, not total events. They are illustrations based on the observed effect, rather than the trial's own original design calculation. The registry record does not report the original design assumptions or sample-size justification. The planning calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect.

The figures are presented for planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For each effect scenario, one column gives the participants per arm for 80% power and another gives the participants per arm for 90% power. In plain terms, those power levels describe the chance, under the planning assumptions and a specified true effect, of detecting an effect at the chosen significance level. They are not probabilities that a treatment works, and they do not describe the chance that the observed trial result is correct.

The illustration gives 8,570,972 participants per arm for 80% power and 11,474,099 per arm for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the corresponding figures are 15,234,497 and 20,394,668 participants per arm. For 50% of the observed effect, they are 34,271,344 and 45,879,605 participants per arm. Smaller effects require more participants under these assumptions, which is why the planning figures increase as the target fraction of the observed effect decreases.

These calculations are not observed power. They are forward-looking planning illustrations, and their very large values reflect the small observed difference used as the starting point. They should not be interpreted as the trial's enrollment target or as evidence that the trial was designed around these numbers. The record does not report the assumptions used for the original trial design.

12. 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 = 0.738; treatment proportion p₁ = 0.738; average p̄ = 0.738.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6220 = 1.2191.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6220 = 0.5235.
4. n = (1.2191 + 0.5235)² / (-0.0006)² = 8,570,971.6, rounded up to 8,570,972 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 <- 0.738095238095238                          # control proportion
p1 <- 0.7375                          # 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(2165202)
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 = 8,570,972 (80% power), 11,474,099 (90% power)
 75% of observed effect: n per arm = 15,234,497 (80% power), 20,394,668 (90% power)
 50% of observed effect: n per arm = 34,271,344 (80% power), 45,879,605 (90% power)
power.prop.test: 8570972 
Simulated power at n = 8,570,972 per arm: 0.801 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and no posted secondary outcomes. It also records no posted analyses. These entries do not establish that no additional outcomes or analyses were considered during the study; they describe what is recorded in the registry record. The record does not report a statistical analysis plan that would specify how multiple outcomes, subgroups, or repeated assessments were handled.

Multiplicity arises when several hypotheses or comparisons are tested. In general, testing many hypotheses can increase the chance of at least one apparently positive result by chance, so a prespecified strategy may control or otherwise address that issue. Since only one primary outcome is posted and no analyses are listed, it is not possible to determine from this record whether multiplicity adjustments were planned or needed for the broader study. The unadjusted p-value for the primary comparison should not be treated as a comprehensive account of every analysis the investigators may have conducted.

The primary population is defined as participants who received at least one injection and were followed up to 52 weeks. The registry record does not state whether the main analysis followed intention-to-treat, per-protocol, or another named principle. It does not report the number randomized to each group, participant flow from randomization into the endpoint analysis, or reasons participants may not have met the analysis-population definition. The overall enrollment figure should not be substituted for the group-specific endpoint denominators.

Missing-data handling is not reported in the registry record. In particular, the record does not explain how incomplete follow-up or unavailable event assessments were treated, whether imputation was used, or whether sensitivity analyses tested alternative assumptions. General statistical concern: when outcome availability is related to group assignment or participants' event experience, analysis of only those with available follow-up can affect the comparison. The record does not show that this occurred, and it does not provide enough information to assess the possibility.

The registry also does not report the original analysis plan, interim analyses, or a multiplicity-control procedure. Those items should be considered unknown rather than inferred from the single posted primary comparison.

14. 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: pancreatitis acute (2.2%), pancreatitis (2.2%), gastroenteritis (1.1%), haemorrhagic stroke (1.1%), overdose (1.1%).

The serious-adverse-event summary reports 4 affected participants among 91 at risk in the rilpivirine group and 1 among 45 at risk in the placebo group. The separate summary for other adverse events reports 80 affected participants among 80 at risk in the rilpivirine group and 40 among 42 at risk in the placebo group. Deaths are listed as 1 in the rilpivirine group and 0 in the placebo group. These are separate summaries with their own reported denominators; they should not be combined or treated as if they describe the primary endpoint's analysis population.

The serious-event terms with the largest reported percentages include Pancreatitis acute and Pancreatitis, each listed at 2.2%, followed by Gastroenteritis, Haemorrhagic stroke, Overdose, and Radius fracture, each listed at 1.1%. The record does not explain whether the two pancreatitis terms refer to separate participants, overlapping categories, or coding distinctions. They should not be added together. Nor should listed percentages be used to infer event counts or participant totals beyond the specific serious-adverse-event summary.

In general, adverse-event summaries describe events recorded during the study; they do not by themselves establish causation. The registry record does not report, alongside these figures, a detailed account of event relatedness, timing, duration, or clinical course. Different denominators across summaries mean that the figures answer different counting questions and require separate interpretation.

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

The posted primary result describes the proportion of the endpoint analysis population that experienced at least one Grade 2 or higher clinical or laboratory adverse event through Week 52. The observed counts are 59 among 80 participants in the rilpivirine group and 31 among 42 participants in the placebo group. The unadjusted comparison has a p-value of 0.994, and the risk-difference interval includes zero while extending in both directions. The result therefore shows little observed separation between the groups on this particular endpoint, with uncertainty about the direction and size of any underlying difference.

That interpretation is narrower than a claim that the products are equally safe. The endpoint combines qualifying events rather than presenting their types, timing, recurrence, or relationship to treatment. Serious adverse events and deaths are reported separately. The posted primary outcome also applies to participants who received at least one injection and were followed up to 52 weeks; it does not automatically represent every randomized participant. Details about missing follow-up and the handling of incomplete outcome data are not reported in the registry record.

The trial title and description include safety and acceptability, but the primary result concerns safety. This outcome does not establish acceptability, effectiveness for preventing HIV, or effects on outcomes that are not posted. The record does not provide a non-inferiority or equivalence margin, so a non-significant result should not be translated into a formal conclusion of equivalence.

The most appropriate reading is descriptive and bounded: the posted groups had similar observed counts for the defined adverse-event outcome, and the statistical comparison does not show a clear difference. The confidence interval and the limitations of the analysis population leave uncertainty. The result should not be extended beyond the recorded endpoint, follow-up period, and study population.

16. Why This Trial Matters Statistically

This trial illustrates why a group comparison needs more than a p-value. The primary comparison's p-value is 0.994, while the risk-difference estimate is close to zero and its confidence interval includes values on both sides of no difference. Read together, these statistics distinguish a small observed separation from certainty about the underlying difference. A high p-value alone does not establish equivalence, and an interval that includes zero does not show that every clinically relevant difference has been excluded.

The endpoint also demonstrates the importance of defining what is counted. The primary measure is the number of participants with any Grade 2 or higher clinical or laboratory adverse event, not the number of event episodes. That is a useful summary for a safety comparison, but it compresses diverse experiences into one indicator. Separate serious-event figures address another aspect of safety and use different denominators, so they cannot be substituted for the primary measure.

The record's population definition is statistically important: inclusion in the primary analysis required at least one injection and follow-up to 52 weeks. The registry does not report the flow from enrollment to that analysis set or how missing observations were handled. Those details affect the context in which the posted counts and uncertainty should be read.

Finally, the record contains a design-label mismatch: it describes a randomized, double-blind, two-arm study while identifying the model as single group. This is a reminder that registry fields can require cautious reading alongside the trial description and posted results. Clear interpretation depends on attending to both the numerical comparison and the completeness and consistency of the record.

17. Limitations

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

The registry record does not resolve the mismatch between its randomized, double-blind, two-arm description and its single-group study-model label. It also does not provide enough detail to reconstruct randomization procedures, allocation concealment, or how blinding was maintained. These omissions constrain assessment of the design beyond its broad description.

The overall enrollment is 136, whereas the primary endpoint analysis reports 80 participants in the rilpivirine group and 42 in the placebo group. The endpoint population is defined as participants who received at least one injection and were followed up to 52 weeks, but participant flow and reasons for non-inclusion are not reported. Missing-data handling and sensitivity analyses are also not reported in the registry record. As a result, the extent to which incomplete follow-up could affect interpretation cannot be assessed from the posted information.

The primary endpoint combines clinical and laboratory events at Grade 2 or higher. The record does not provide a full breakdown of this outcome by event type, timing, severity within the qualifying range, or assessed relationship to treatment. The serious-event listing is a separate summary, with denominators that differ from those used for the primary endpoint. The record does not explain all coding details or overlap among listed serious-event terms.

No primary analysis plan, original sample-size justification, equivalence margin, or multiplicity procedure is reported. The posted comparison is unadjusted, and no posted secondary outcomes or analyses are listed. The registry record also does not provide an acceptability result, despite acceptability being part of the study title and purpose. These limitations mean that conclusions should remain restricted to the posted primary safety count and its stated follow-up.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278LA, for Pre-Exposure Prophylaxis — NCT02165202.
• Registry record last updated 2018-08-27; status last verified 2018-07.
• Results first posted 2018-07-26.
• 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.

21. Record Summary

NCT02165202 is a completed Phase II study sponsored by PATH. The registry describes a multisite, randomized, double-blind comparison of TMC278 LA and placebo in sexually active, HIV-uninfected women, with two:one allocation. It lists enrollment as 136 and identifies safety and acceptability in pre-exposure prophylaxis as the study focus. Its model field is recorded as single group despite the two-arm description.

The primary endpoint counts participants with any Grade 2 or higher clinical or laboratory adverse event through Week 52. The analysis includes participants who received at least one injection and were followed up to 52 weeks. The posted counts are 59 among 80 in the rilpivirine group and 31 among 42 in the placebo group; the unadjusted p-value is 0.994. The confidence interval for the risk difference includes zero and extends in both directions. The record does not report the original sample-size justification, missing-data approach, or detailed analysis plan.