A Trial With TMC278-TIDP6-C222 for Continued TMC278 Access in Patients Infected With Human Immunodeficiency Virus-1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial With TMC278-TIDP6-C222 for Continued TMC278 Access in Patients Infected With Human Immunodeficiency Virus-1 (NCT01266902), a na phase 3 study. The primary outcome is Number of Participants With Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This completed Phase 3 study was an open-label, single-group trial of continued TMC278 access. Its stated purpose was to allow participants with HIV-1 who had been randomized and treated with TMC278 in earlier Phase IIb or Phase III trials to continue access while still benefiting from treatment. The registered intervention was rilpivirine 25 mg once daily, with a background regimen containing 2 N(t)RTI's.

The registry records enrollment of 482 and dates of 2011-02 for study start and 2020-02 for primary completion. Those entries describe the overall registration, not the number of participants included in each adverse-event cohort. The trial was completed, had no masking, and is classified as single-group. Allocation is recorded as NA.

Adverse-event results are separated by earlier trial participation: TMC278-C204 [C204], and TMC278-TiDP6-C209 [C209] and TMC278-TiDP6-C215 [C215]. These group labels preserve the source-cohort distinction. They do not create a randomized comparison, and differences between their recorded counts cannot be interpreted as treatment effects or as evidence that one cohort had greater risk. The cohorts may differ in their origins and circumstances; further details about those differences are not reported in the registry record.

The primary endpoint is the number of participants with adverse events, over a timeframe of up to 7 years. The registry also lists secondary outcomes concerning virologic rebound, treatment failure, CD4+ cell-count change, serious adverse events, and adverse events related to rilpivirine. The available record does not report a statistical analysis plan, endpoint results for those secondary outcomes, or a detailed account of how participants entered or left the continued-access trial.

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: Total of 482 participants were treated and 437 discontinued at data cut-off date (8 February 2018) because they switched to commercially available rilpivirine (RPV) (371 participants), as planned per protocol. Only 6 of the 482 participants discontinued as they reached a virologic endpoint. At last contact date of last participant under Protocol Amendment 3 (28 February 2020), out of 45 participants 37 switched to commercially available RPV and 6 were lost to follow-up.

Period 1 (Main Study)

Reasons for not completing this period:

Period 2 (After Protocol Amendment 3)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The intent-to-treat (ITT) population included all participants who have taken at least 1 dose of rilpivirine (RPV), regardless of their compliance with the protocol and adherence to the dosing regimens.

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 Number of Participants With Adverse Events (AEs), measured over Up to 7 years.

The primary endpoint counts participants with adverse events during a timeframe of up to 7 years. The registry defines an adverse event as an unfavorable and unintended sign, symptom, or disease temporally associated with use of a medicinal product, whether or not the event is considered related to that product. This definition includes abnormal findings and does not require investigators to conclude that rilpivirine caused the event.

A participant count is a binary-outcome summary: for the endpoint, a participant is classified according to whether an adverse event was recorded. It is not a count of all separate episodes, and it does not describe how long an event lasted, how serious it was, or whether it led to treatment discontinuation. The record separately identifies serious and other adverse-event counts, which adds information about event classification but does not replace the broader primary endpoint definition.

This endpoint is useful for describing the safety experience recorded during continued treatment. Its meaning is descriptive in this single-group study. Without a randomized comparator and an inferential analysis, the count cannot establish the excess or reduction in events attributable to rilpivirine. Nor does it alone distinguish events related to treatment from events that occurred during treatment for other reasons. The registry does not report a pooled primary endpoint count across the cohorts.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is expressed as a number of participants with an event. In statistical terms, this is a binary outcome at the participant level: the endpoint records whether an adverse event was experienced, rather than how many event episodes each participant had. The registry provides counts by earlier-trial cohort and gives an at-risk count for each adverse-event category. A count is directly descriptive, but it does not itself quantify uncertainty or support a causal interpretation.

For a binary outcome, researchers may present a proportion, a difference between proportions, a relative measure, or a model-based estimate. Such summaries need a clearly defined numerator, denominator, population, and observation period. The record does not report a pooled primary endpoint estimate, a treatment-effect estimate, or confidence intervals. No new proportion, difference, or ratio is calculated in this interpretation. Without an appropriate comparison group, even a precisely measured event frequency would describe the observed cohort rather than an effect of treatment.

In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision for that estimate, while a wider interval indicates less precision. An interval is not reported for the adverse-event results in the registry record, so the precision of a comparison or effect cannot be judged from interval estimates. The record also contains no inferential analysis entries. This means the posted adverse-event counts should be read as descriptive summaries rather than as findings from a reported significance test.

The trial classification matters for choosing an interpretation. It is registered as a single-group, open-label study, with allocation recorded as NA and masking recorded as none. It therefore does not provide a randomized, masked comparison between rilpivirine and another treatment. The C204 and C209/C215 categories identify participant cohorts by earlier study participation. They do not represent randomized arms within this continued-access study. General statistical practice would require attention to baseline differences, follow-up, and outcome ascertainment before comparing such cohorts; those details and any adjustment for them are not reported in the registry record.

The registry describes the primary analysis population as intent-to-treat participants who took at least one rilpivirine dose, regardless of protocol compliance or adherence. This definition sets a population for the primary endpoint, but it does not explain how missing adverse-event observations were handled, whether follow-up was complete, or how participants with differing observation times were represented in the counts. The timeframe is up to 7 years, which signals an extended observation window; the record does not give participant-level follow-up durations or a time-adjusted event rate. Counts accumulated over differing observation periods can be difficult to compare without additional information.

Several secondary outcomes are time-to-event outcomes, including time to virologic rebound and time to treatment failure. In general, time-to-event methods account for the timing of an event and can also handle participants whose event time is not observed by the end of follow-up, subject to specified assumptions. The registry does not report the methods, estimates, event counts, censoring rules, or analyses for these outcomes. No time-to-event conclusion can therefore be drawn from their titles alone.

The listed CD4+ outcomes use two named approaches: observed case through Week 336 and non-completer equals failure (NC=F) through Week 336. In general, an observed-case approach uses available measurements, whereas a non-completer-equals-failure convention assigns a specified outcome to participants who do not complete, according to the stated rule. The approaches can produce different summaries because they treat missing follow-up differently. The registry does not report the resulting CD4+ estimates, the detailed implementation, or additional missing-data assumptions. The labels should not be taken as evidence that a particular method is unbiased or that missingness has been resolved.

The record lists 8 outcome measures and 0 analyses. It does not report a multiplicity procedure, a hierarchy of confirmatory outcomes, or a statistical analysis plan. In general, when multiple outcomes or tests are examined, multiplicity methods may be used to control the chance of false-positive findings across a family of tests. Since the analyses and testing strategy are not reported, no claim about such control is justified.

The registry's sample-size assumptions describe planning illustrations based on an observed effect: two-sided significance level 0.05, equal allocation, and a normal approximation, with the effect to detect stated as a fraction of the observed effect. Such illustrations are hypothetical planning calculations, not observed power and not evidence that the trial was designed around those assumptions. They do not convert this single-group continued-access study into a randomized comparison. The actual sample-size justification and a trial-specific statistical plan are not reported in the registry record.

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("Rilpivirine (RPV) (TMC278-C204 [C204])", "RPV (TMC278-TiDP6-C209 [C209] and TMC278-TiDP6-C21")
n      <- c(119, 363)
events <- c(32, 70)
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  Rilpivirine (RPV) (TMC278-C204 [C204])  119  32  26.9  19.2  35.8  19.7  35.5  19.7  35.5
ARM  RPV (TMC278-TiDP6-C209 [C209] and TMC278-TiDP6-C21  363  70  19.3  15.4  23.7  15.6  23.7  15.6  23.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and records 0 analyses. It names the primary adverse-event endpoint and several secondary outcomes, but does not report a testing hierarchy, a family of confirmatory hypotheses, or a multiplicity adjustment. In general, multiplicity refers to the increased chance of a false-positive result when several hypotheses are tested. Statistical methods can address that issue when the analyses and testing strategy are specified. Since those details are not reported in the registry record, it is not possible to determine whether multiplicity was considered or how it would affect interpretation.

The primary population is described as participants who took at least one dose of rilpivirine, regardless of protocol compliance or adherence. This defines who is included in the stated intent-to-treat population, but the record does not provide a detailed flow of participants, completeness of outcome observation, or handling of missing adverse-event data. It also does not state how participants with different lengths of follow-up contributed to the event counts.

The names of the CD4+ secondary outcomes refer to an observed-case approach and an NC=F approach through Week 336. These labels indicate different conventions for handling non-completion, but the record does not provide the outcome estimates or enough methodological detail to assess implementation. No imputation strategy, sensitivity analysis, or assessment of missingness is reported. Missing-data methods for the other endpoints are also not reported in the registry record.

These omissions limit how completely the endpoint definitions and analysis population can be evaluated. They do not establish that data were missing or that any particular method was used; they mean that the corresponding details are not reported.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: coronary artery disease (0.8%), abdominal discomfort (0.8%), gastrooesophageal reflux disease (0.8%), chest pain (0.8%), cholelithiasis (0.8%).

The serious adverse-event counts are 9 among 119 at risk in the C204 cohort and 16 among 363 at risk in the cohort from C209 and C215. The registry also records 0 and 2 deaths in those respective cohorts. These are descriptive entries for the identified groups. They should not be read as a comparison of treatment effects because the study is single-group and the groups are based on participation in earlier trials, not randomization within this study.

The record separately lists 25 participants with other adverse events in the C204 cohort and 61 in the C209 and C215 cohort, with at-risk counts of 119 and 363. It does not establish in the available summary whether these categories are mutually exclusive or how they relate to the primary endpoint's overall count. Adding the categories would therefore be inappropriate. The primary adverse-event definition also includes events regardless of whether they are considered related to the medicinal product.

The serious-event terms listed include coronary artery disease, abdominal discomfort, gastrooesophageal reflux disease, chest pain, cholelithiasis, and dengue fever; each is recorded as 0.8%. These entries identify reported terms, not proof of causation or a complete characterization of risk. The registry does not report event-level narratives, exposure-adjusted rates, or an inferential safety comparison. Counts should be interpreted as observed during the stated continued-access study, not as estimates of what rilpivirine caused.

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

The results give a descriptive account of adverse events recorded among people continuing rilpivirine after earlier TMC278 trial participation. They include serious and other adverse-event counts by earlier-trial cohort, along with the registered at-risk counts and deaths. The serious-event terms and their recorded percentages add examples of the types of events appearing in the safety record. These summaries are relevant to understanding what was recorded during continued access, but they do not provide a causal estimate.

The study design sets an important boundary on interpretation. There is no randomized comparator, and the C204 and C209/C215 cohorts are not like-for-like control arms. Consequently, the results cannot show whether event frequency was higher or lower because of rilpivirine, as opposed to what might have occurred in the absence of treatment. The record also does not report an adjusted comparison, an effect estimate, or confidence intervals that would quantify the precision of a treatment contrast.

The primary endpoint counts participants with adverse events, including events not judged related to the medicinal product. The separate listing of serious events and other events does not, by itself, resolve attribution or provide a complete account of severity, duration, recurrence, or clinical consequences. The listed serious-event terms are descriptive registry entries; their presence does not establish that rilpivirine caused them.

The record's stated timeframe extends up to 7 years, but detailed follow-up durations and methods for accounting for varying observation time are not reported. The secondary outcomes include virologic, treatment-failure, CD4+ and safety measures, but their estimates and analysis results are not present in the reported record. Their inclusion as registered outcomes should not be mistaken for evidence of a particular result.

Overall, the posted data describe the safety experience recorded in a continued-access study population. They do not establish treatment benefit, absence of harm, or a comparative risk attributable to rilpivirine. Those conclusions would require information and analyses that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable because its purpose and design are descriptive rather than comparative. Continued access for participants who were still benefiting from treatment can generate useful longitudinal safety information, while the single-group, open-label structure limits causal inference. Recognizing that distinction helps prevent raw cohort counts from being mistaken for randomized evidence.

The earlier-trial labels are also important. The registry reports adverse-event experience separately for the C204 cohort and the C209/C215 cohort, retaining information about where participants came from. That stratification can make the descriptive record easier to interpret, but it does not eliminate differences between cohorts or create a valid concurrent control group. A numerical contrast between these cohorts would not, on its own, estimate a treatment effect.

The endpoint definition illustrates why safety counts require careful reading. The primary outcome includes adverse events whether or not they are considered related to the medicinal product. Serious events and other events are reported separately, while rilpivirine-related adverse events are named as a secondary outcome. Distinguishing occurrence from attribution is essential: an event recorded during treatment is not automatically an event caused by treatment.

The registry also illustrates the difference between registered outcomes and reported analyses. It names time-to-event and CD4+ outcomes, yet records no analyses. Without estimates, uncertainty measures, missing-data details, or a statistical plan, outcome names alone cannot support conclusions. The record's planning assumptions are likewise not observed power or evidence of a prespecified comparative design.

For biostatistical interpretation, the central lesson is to match claims to design and reporting. These data support a description of recorded adverse events in the continued-access cohorts. They do not support an inferential treatment comparison or a causal conclusion.

15. Limitations

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

The main limitation for interpretation is the absence of a randomized comparator. The study is registered as single-group, open-label, with allocation recorded as NA and no masking. The cohort categories reflect earlier trial participation and cannot serve as randomized treatment and control groups. Raw differences between their event counts are not causal estimates.

The registry record does not report confidence intervals, hypothesis tests, adjusted estimates, or an analysis plan. It gives adverse-event counts and at-risk counts by cohort, but does not report a pooled primary endpoint count. The available summary also does not clarify whether serious and other event categories are mutually exclusive, so their counts should not be combined.

Follow-up is described as extending up to 7 years, but the record does not report individual or cohort-level follow-up duration, exposure-adjusted event rates, or procedures for handling varying observation time. It also does not report detailed missing-data methods for the primary endpoint. These omissions limit evaluation of how completely events were observed over time.

The serious-event terms are listed with percentages, but their denominators and the full details of event ascertainment are not reported alongside those entries. The record does not provide enough information to assess whether event differences reflect clinical characteristics, observation, or other cohort features. It also does not report the results for the registered secondary virologic, treatment-failure, and CD4+ outcomes.

Finally, the registry's planning assumptions do not establish the trial's original sample-size rationale or statistical design. A trial-specific justification, interim-analysis strategy, and detailed statistical plan are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Trial With TMC278-TIDP6-C222 for Continued TMC278 Access in Patients Infected With Human Immunodeficiency Virus-1 — NCT01266902.
• Registry record last updated 2021-03-04; status last verified 2021-02.
• Results first posted 2021-03-04.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01266902 is a completed Phase 3, open-label, single-group trial of continued rilpivirine access for people with HIV-1 who participated in earlier TMC278 trials and were still benefiting from treatment. The registered intervention was rilpivirine 25 mg once daily in combination with a background regimen containing 2 N(t)RTI's. Enrollment is recorded as 482; the study start is listed as 2011-02 and primary completion as 2020-02.

The primary endpoint is the number of participants with adverse events over up to 7 years. The registry describes the intent-to-treat population as participants who took at least one dose of rilpivirine. Adverse-event counts are listed by earlier-trial cohort, with separate serious and other event entries and recorded deaths. The study has no randomized comparator, and the registry records 0 analyses. It does not report inferential estimates, confidence intervals, a statistical analysis plan, or detailed missing-data methods. Its safety figures are therefore descriptive and should not be interpreted as a causal comparison.