A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1 (NCT00823979), a randomized phase 2 study. The primary outcome is Percentage of Participants With Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 50 Copies/Milliliter (mL) at Week 24.

2. Clinical Question

The clinical question is comparative: it concerns virologic response under the assigned regimens, not the effect of either study drug in isolation. The background drugs were part of both combinations, so the posted group outcomes represent the regimens as studied. The primary measure treats participants who met specified discontinuation, follow-up, treatment-change, or missing-result conditions as failures. This means the percentage is an outcome under the registry's stated classification rule, rather than a percentage calculated only among participants with a measured Week 24 viral load.

The trial included two lersivirine dose groups and an etravirine comparator group. The central comparison for the clinical question is each lersivirine group against etravirine; the registry record also reports a comparison between the 1000 mg lersivirine group and the 750 mg group. Results describe the observed participants and do not, on their own, establish what would happen in a different population or with a different background regimen.

3. Trial Design

The registry identifies NCT00823979 as a randomized, double-blind, parallel Phase 2b comparative trial. It lists enrollment of 105 participants and HIV-1 as the condition. The intervention groups were lersivirine 750 mg, lersivirine 1000 mg, and etravirine 200 mg. The registry title identifies the study drug as UK-453,061; the posted arm labels use the name lersivirine. Each regimen was intended to be combined with darunavir/ritonavir and a nucleos(t)ide reverse transcriptase inhibitor.

The brief summary describes a 96 week study. The primary endpoint was assessed at Week 24, and listed secondary outcomes include assessments at later time points, including Week 48 and Week 96. The record gives a start date of 2009-03-25 and a primary completion date of 2012-10-18. Its status is terminated. The reason for termination and the original trial-specific sample-size justification are not reported in the registry record.

For the primary outcome, the posted arm sizes are 31 for lersivirine 750 mg, 32 for lersivirine 1000 mg, and 34 for etravirine 200 mg. These are the denominators stated with the primary outcome results; they should not be confused with the enrollment figure. The registry describes the primary analysis population as intention-to-treat. Its outcome rule classified certain events, including death, discontinuation, loss to follow-up, a prohibited antiretroviral drug change, and missing Week 24 HIV-1 RNA data, as virologic failure.

The arm descriptions contain no further regimen details. The registry record does not report the randomization method, allocation ratio, concealment procedure, blinding procedures, or detailed eligibility criteria beyond the antiretroviral experience and NNRTI-resistance description. These details therefore cannot be used to refine the design interpretation.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population. Participants who died, discontinued, lost to follow-up, switched/changed dose of anti-retro viral (ARV) drug not allowed by protocol, had missing plasma HIV-1 RNA data at 24 weeks were considered to have plasma HIV-1 RNA \>=50 copies/mL and were referred to as failure.

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: Intent-to-Treat (ITT) population included all randomized participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 50 Copies/Milliliter (mL) at Week 24, measured over Week 24.

The primary endpoint is the percentage of participants with HIV-1 RNA below 50 copies/mL at Week 24. HIV-1 RNA is a measure of virus in plasma; the registry states that it was determined using the Roche Amplicor HIV-1 Monitor standard assay, version 1.5. A threshold endpoint divides participants according to whether their measured or classified viral load is below the stated cutoff. It gives a readily interpretable group-level summary of virologic response at a defined time point.

The registry specifies an intention-to-treat population and a failure rule for participants who died, discontinued, were lost to follow-up, changed or switched an antiretroviral drug in a way not allowed by protocol, or had missing plasma HIV-1 RNA data at Week 24. These participants were considered to have HIV-1 RNA at or above 50 copies/mL and counted as failures. Thus, the reported percentage reflects both the viral-load criterion and this handling of incomplete follow-up or treatment changes.

As a general statistical point, a binary threshold endpoint is simple to compare across groups, but it discards information about how far individual measurements are from the cutoff. The registry also lists continuous changes in log10-transformed HIV-1 RNA and other virologic measures as secondary outcomes. Those measures address related questions in different ways; they do not replace the specified primary endpoint. The registry does not report a rationale for selecting the Week 24 threshold as the primary measure.

7. Results Posted in the Registry

• Lersivirine 1000 mg: 43.8% (14/32) versus 48.4% (15/31) on control; risk difference -4.6 percentage points (95% CI -29.2 to 20.0), risk ratio 0.90 (0.53–1.54); unadjusted two-proportion z-test p = 0.712.
• Etravirine 200 mg: 67.6% (23/34) versus 48.4% (15/31) on control; risk difference 19.3 percentage points (95% CI -4.3 to 42.9), risk ratio 1.40 (0.91–2.15); unadjusted two-proportion z-test p = 0.116.

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.

Number of Participants With Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Resistance-Associated Mutations (RAMs) and/or Phenotypic Susceptibility at Time of Treatment Failure Through Week 48

• 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:
  • Lersivirine 1000 mg: 18.8% (3/16) versus 41.7% (5/12) on control; risk difference -22.9 percentage points (95% CI -56.7 to 10.9), risk ratio 0.45 (0.13–1.52); unadjusted two-proportion z-test p = 0.184.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lersivirine 1000 mg and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Laboratory Test Abnormalities

• 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:
  • Lersivirine 1000 mg: 96.8% (30/31) versus 93.1% (27/29) on control; risk difference 3.7 percentage points (95% CI -7.5 to 14.8), risk ratio 1.04 (0.92–1.17); unadjusted two-proportion z-test p = 0.514.
  • Etravirine 200 mg: 97.1% (33/34) versus 93.1% (27/29) on control; risk difference 4.0 percentage points (95% CI -6.9 to 14.8), risk ratio 1.04 (0.93–1.17); unadjusted two-proportion z-test p = 0.462.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lersivirine 1000 mg 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 Etravirine 200 mg and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover several dimensions of HIV-1 treatment response. The registry lists additional viral-load thresholds and time points, change in log10-transformed HIV-1 RNA, time-averaged differences, response under a time-to-loss-of-virologic-response algorithm, CD4+ absolute and percentage counts, and resistance-associated mutations or phenotypic susceptibility at treatment failure. Laboratory abnormalities are also posted as a secondary result. Together, these outcomes address virologic response over time, immune measures, resistance at failure, and laboratory findings, rather than repeating the primary Week 24 threshold question.

These measures can provide context for the primary result, but they do not automatically strengthen or overturn it. A secondary measure can differ because it uses another viral-load cutoff, a different time point, a continuous change rather than a threshold, or a subset defined by treatment failure. Each has its own denominator and interpretation. The registry lists 11 secondary outcome measures, while detailed posted results in the record include outcomes on resistance-associated mutations or phenotypic susceptibility at treatment failure and laboratory test abnormalities. The record does not report analysis entries for the secondary outcomes.

As a general statistical principle, secondary findings carry less weight when many measures or time points are examined without a prespecified hierarchy or multiplicity adjustment. An isolated pattern may be unstable, especially when subgroup denominators are small. The registry does not report a multiplicity plan, so the listed secondary outcomes are best treated as descriptive or supportive rather than as a set of independent confirmatory tests. They should be interpreted alongside the primary endpoint definition, the study's terminated status, and the lack of registry-reported details about the analysis plan.

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

• Percentage of Participants With HIV-1 RNA Levels <50 Copies/mL at Week 48 and 96
• Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL at Week 24, 48 and 96
• Change From Baseline in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96
• Time-Averaged Difference (TAD) in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96
• Percentage of Participants With Response as Determined by the Time to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96
• Change From Baseline in Cluster of Differentiation 4 (CD4+) Absolute Lymphocyte Counts at Week 24, 48 and 96
• Change From Baseline in Cluster of Differentiation 4 (CD4+) Percentage Lymphocyte Counts at Week 24, 48, 96
• Number of Participants With Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Resistance-Associated Mutations (RAMs) and/or Phenotypic Susceptibility at Time of Treatment Failure Through Week 48

9. Statistical Interpretation

10. Statistical Methods Explained

The primary result is a binary outcome: each participant is classified as meeting or not meeting the Week 24 HIV-1 RNA threshold. A group percentage describes the share classified as meeting that criterion. The comparative effect reported is a risk difference, which expresses the difference between two group proportions. General statistical interpretation of a risk difference depends on its sign and scale: zero corresponds to equal proportions, while values on either side describe the direction of the estimated contrast. The reported estimates and intervals use the proportion scale.

What does the confidence interval express?

As a general explanation, a confidence interval is a range generated by a statistical procedure intended to reflect the uncertainty in an estimated effect. It is not a range containing a fixed proportion of individual participants' outcomes, and it is not a probability statement about the true effect after the data are observed. Here, the intervals around both primary comparisons are broad and include zero. That means the estimates do not pin down the direction or size of the difference precisely. The registry does not report the method used to construct these intervals, so the specific interval procedure should not be assumed.

How should the p-values be read?

The primary comparisons include unadjusted p-values. In general, a p-value evaluates the compatibility of the observed data with a stated null model, subject to the analysis assumptions. A small p-value is not proof of an effect, and a larger p-value is not proof of equality. Because the primary intervals include zero and the p-values are unadjusted, neither statistic should be treated as a definitive answer by itself. The registry record does not report the exact test or model used for these comparisons.

Why does the endpoint rule matter?

The intention-to-treat endpoint definition assigns failure status to specified events rather than omitting those participants from the Week 24 outcome. This approach preserves a defined analysis population and makes discontinuation, loss to follow-up, prohibited drug changes, and missing Week 24 viral-load measurements part of the outcome classification. As a general matter, such rules affect the estimand: the quantity being compared is the percentage meeting the threshold after applying the stated failure convention. It is not simply the percentage among participants with observed Week 24 measurements.

The record does not report whether additional sensitivity analyses explored alternative assumptions about missing outcomes. It also does not report a detailed statistical analysis plan, adjustment covariates, stratification factors, or model diagnostics. Those absences limit how specifically the reported comparison can be reconstructed. The stated population and failure rule can be described, but the registry does not support claims about unreported analytic choices.

What is the role of the other outcome measures?

The registry lists other virologic measures, including percentages below different HIV-1 RNA thresholds, changes in log10-transformed HIV-1 RNA, and response under a time-to-loss-of-virologic-response algorithm. It also lists CD4+ count outcomes and resistance-associated mutations or phenotypic susceptibility at treatment failure. These measures examine related but distinct features of response, immune-cell measures, and resistance. A consistent pattern across different endpoints can add context, but endpoints with different definitions, time frames, and populations are not interchangeable.

As a general statistical concern, testing many outcomes or contrasts increases the opportunity for apparently notable findings to arise by chance. Multiplicity procedures can control or describe that risk, but the registry record does not report a testing hierarchy, family-wise error adjustment, false-discovery procedure, or other multiplicity plan. Secondary results should therefore be regarded as exploratory or supportive unless the record establishes a confirmatory role. That qualification applies even when a result has a small unadjusted p-value; no such value is reported for the listed secondary results.

What does over-dispersion mean in this setting?

Over-dispersion is a general issue for count data when observed variability exceeds what a simple model assumes. The primary endpoint is binary rather than a count of repeated events, and the registry gives no dispersion parameter or over-dispersion assessment. It would therefore be inappropriate to infer that a particular over-dispersion adjustment was used. For a binary group comparison, the more immediate uncertainty concerns the limited group sizes and the resulting breadth of the risk-difference intervals.

There are no reported analysis entries for the secondary outcomes in the registry. The posted outcome values and comparisons can still be described, but absence of an analysis entry means the record does not establish the precise model, inferential procedure, or confirmatory status for those results. In general, descriptive arm results, effect estimates, confidence intervals, and p-values answer different questions; their interpretation depends on their definitions and the analysis plan. The original analysis plan and sample-size justification are not reported in the registry record.

11. Confidence Intervals and Precision

The Week 24 group percentages are based on relatively small denominators: 31 participants in the lersivirine 750 mg group, 32 in the lersivirine 1000 mg group, and 34 in the etravirine 200 mg group. With a binary outcome, each participant contributes to one of two classifications. When group sizes are limited, a small number of participants can have a visible effect on the estimated proportion, and uncertainty about the population-level proportion remains substantial.

The risk-difference interval for lersivirine 1000 mg compared with lersivirine 750 mg extends from -0.292 to 0.200. The interval for etravirine 200 mg compared with lersivirine 750 mg extends from -0.043 to 0.429. Each interval includes zero and spans values on both sides of it. Their widths indicate that the observed point estimates do not provide a precise estimate of the comparative effect. The interval endpoints are not predictions of the exact outcomes in future participants; they express uncertainty under the interval method, which is not identified in the registry record.

As a general principle, precision and statistical significance are not the same thing. A point estimate can be clinically or scientifically interesting yet imprecise, while a narrow interval can still describe an effect that is modest. The registry does not define a clinically important difference for this endpoint, so these results cannot be judged against a stated clinical threshold. Nor does the interval alone determine whether the regimens should be considered equivalent: equivalence or noninferiority requires a specified margin and an appropriate design and analysis, which are not reported in the registry record.

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 are participants per arm for comparisons of two groups. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect is a stated fraction of the observed effect. For the lersivirine 1000 mg versus lersivirine 750 mg comparison, the estimates range from 1,813 participants per arm for 80% power and 2,427 participants per arm for 90% power when planning for 100% of the observed effect, to 7,277 and 9,742 participants per arm when planning for 50% of the observed effect. For etravirine versus lersivirine 750 mg, the corresponding figures are 102 and 136 participants per arm for the full observed effect, and 421 and 563 for half the observed effect. Planning for 75% of the observed effect gives the intermediate figures listed with each comparison.

In general, power is the probability that a specified analysis will reject its null hypothesis when a particular effect is present, under the assumptions used for the calculation. The 80% and 90% columns describe different target probabilities for detecting the assumed effect; they are not outcomes measured in this trial. A higher target power requires more participants under otherwise unchanged assumptions. Likewise, a smaller effect is harder to distinguish from random variation and requires more participants: the estimates rise as the assumed fraction of the observed effect is reduced.

These figures are planning illustrations based on the observed effect, not the trial's own design calculation. They are not observed power. The original trial's sample-size assumptions, including its intended target effect and any allowance for attrition, are not reported in the registry record. The illustrations do not incorporate any unreported design features or establish what sample size the investigators originally intended.

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 = 0.484; treatment proportion p₁ = 0.438; average p̄ = 0.461.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7049 = 1.3816.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.7042 = 0.5926.
4. n = (1.3816 + 0.5926)² / (-0.0464)² = 1,812.6, rounded up to 1,813 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 <- 0.483870967741935                          # control proportion
p1 <- 0.4375                          # 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(823979)
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 = 1,813 (80% power), 2,427 (90% power)
 75% of observed effect: n per arm = 3,229 (80% power), 4,323 (90% power)
 50% of observed effect: n per arm = 7,277 (80% power), 9,742 (90% power)
power.prop.test: 1812.6 
Simulated power at n = 1,813 per arm: 0.804 (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 how multiplicity was handled. In particular, it does not state whether the two lersivirine doses were tested under a formal hierarchy, whether the primary comparisons shared an error-rate allocation, or whether any adjustment was applied across secondary outcomes and time points. The record lists a range of virologic, immune, resistance, and laboratory outcomes. Without a stated testing plan, unadjusted comparisons should not be read as if each were the sole prespecified test.

Multiplicity matters because repeated testing creates more opportunities for results that appear unusual under a no-effect model. This is a general statistical issue, not evidence that any specific finding in this trial is spurious. A prespecified hierarchy or adjustment can help define which questions are confirmatory and how evidence should be interpreted. Such procedures are not reported in the registry record. The analysis plan, any interim analyses, and any stopping rules are also not reported in the registry record.

The primary outcome population and missing-data convention are described. The intention-to-treat population included participants who died, discontinued, were lost to follow-up, changed or switched an antiretroviral drug in a way not allowed by protocol, or had missing plasma HIV-1 RNA data at Week 24 as failures, classified as having HIV-1 RNA at or above 50 copies/mL. This is an explicit endpoint rule, but the registry does not describe additional sensitivity analyses or alternative missing-data assumptions. The record also does not report whether the analysis used any adjustment for baseline variables or study strata.

The distinction is important: a stated failure convention does not reveal every part of the statistical method, and an intention-to-treat label does not by itself specify an estimator, test, or model. The registry provides a defined way to classify specified missing or treatment-related outcomes, but further details of the analysis population beyond that description and the original statistical plan are not reported. The reason for trial termination is also not reported, so no link between termination and an interim analysis or outcome can be inferred.

15. Safety Results

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

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: pulmonary tuberculosis (6.2%), hypertension (3.2%), coronary artery disease (3.1%), head injury (3.1%), pneumocystis jiroveci pneumonia (2.9%).

The posted serious adverse event figures list 1 affected participant among 31 at risk in the lersivirine 750 mg group, 4 among 32 in the lersivirine 1000 mg group, and 1 among 34 in the etravirine 200 mg group. These are group-level counts as recorded; they do not establish that the events were caused by the assigned treatment. The registry does not report a comparative safety analysis or a formal statistical test for these counts.

The record lists pulmonary tuberculosis at 6.2%, hypertension at 3.2%, coronary artery disease at 3.1%, head injury at 3.1%, Pneumocystis jiroveci pneumonia at 2.9%, and pneumonia at 2.9% among the top serious terms. The registry does not provide enough detail in these entries to infer the relationship of each term to a specific treatment group or the basis of the percentages. Death counts are not reported in the registry record.

As a general point, serious adverse event counts are descriptive safety information. Their interpretation depends on exposure, follow-up, event definitions, and the completeness of reporting. These details and the reason for termination are not reported in the registry record. The figures should therefore be read as recorded events, not as a complete causal comparison or a basis for individual treatment decisions.

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

The result describes the proportion classified as having HIV-1 RNA below 50 copies/mL at Week 24 in each randomized group, using the registry's failure rule for specified events and missing measurements. The observed percentages were 48.4% for lersivirine 750 mg, 43.8% for lersivirine 1000 mg, and 67.6% for etravirine 200 mg. The comparative estimates have broad confidence intervals that include zero. The data therefore describe a difference in the observed group percentages, while leaving substantial uncertainty about the size and direction of the underlying group differences.

These results do not by themselves establish that one regimen is superior, equivalent, or noninferior to another. Such conclusions require a suitable prespecified question, an analysis that matches that question, and, for equivalence or noninferiority, an explicitly defined margin. The registry does not report such a margin or the detailed analysis plan. An unadjusted p-value also cannot establish that a treatment effect exists or is absent.

The finding is specific to antiretroviral-experienced participants with evidence of NNRTI resistance who were studied with the background regimen described in the record. It should not be generalized automatically to people with different treatment histories, resistance profiles, or background therapy. The trial's terminated status and the reason for termination is not reported in the registry record. The Week 24 primary result also does not supply results for the later time points listed among secondary outcomes.

Safety information has separate limits. The serious adverse event counts are descriptive and do not establish treatment causality. The registry does not report deaths, a detailed comparative safety analysis, or the reason for termination. Taken together, the posted data are useful for describing the trial's endpoint definitions and observed results, but they do not answer every clinical, long-term, or causal question about the regimens.

17. Why This Trial Matters Statistically

This trial illustrates why an observed percentage and a comparative effect estimate should be read together. The arm percentages communicate the observed response under the defined endpoint, while the risk differences quantify the group contrasts. The confidence intervals show that the estimates are uncertain; a point estimate alone would conceal that uncertainty. The registry's stated intention-to-treat rule also matters because it classifies participants with specified missing or treatment-related outcomes as failures rather than excluding them from the primary endpoint.

The record offers a useful example of the distinction between a randomized design and a fully documented analysis. Randomization and double masking are recorded, but details of allocation, the analysis model, multiplicity handling, and the original sample-size justification are not reported. A registry may therefore document some design features and outcome results without providing every element needed to reproduce or fully assess the inferential plan.

The planning illustrations also demonstrate how sample-size requirements depend on the effect assumed in advance. Smaller assumed effects require larger groups to achieve the stated power targets under the specified calculation assumptions. Those planning figures are not evidence that the completed trial had a particular probability of detecting an effect, nor do they reveal the investigators' original design rationale.

Finally, the study's terminated status highlights the importance of separating a recorded status from an explanation. Without a reported reason, it cannot be tied to the results, safety events, or a planned interim decision. For statistical interpretation, the essential lesson is to keep endpoint definition, uncertainty, analysis-plan information, and registry completeness distinct rather than allowing any one feature to stand in for the others.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary comparisons are based on small group denominators, and their confidence intervals are broad. That limits precision about the comparative effects. The registry does not report a clinically important difference for the Week 24 endpoint, so the observed estimates cannot be evaluated against a stated threshold for practical importance. The trial is identified as Phase 2b and terminated; the reason for termination is not reported in the registry record.

Some design and analysis details needed for a fuller appraisal are absent. The randomization procedure, allocation ratio, concealment, blinding procedures, detailed eligibility criteria, statistical model, interval method, covariate adjustment, and multiplicity strategy are not reported in the registry record. The record also does not report the original sample-size justification, interim analyses, stopping rules, or sensitivity analyses for missing outcomes. The primary endpoint does specify a failure classification for certain missing and treatment-related events, but alternative assumptions are not described.

The registry lists a broad set of secondary outcomes and later time points, while the detailed posted secondary results are limited. Results for outcomes not included in the posted entries cannot be inferred from the primary endpoint. Secondary outcomes also differ in their definitions and denominators, making a single overall secondary pattern difficult to characterize. The absence of reported analysis entries further limits assessment of how those outcomes were analyzed.

Safety reporting is descriptive in the available record. Serious adverse event counts are posted, but the registry does not report deaths or a comparative safety analysis, and the relationship of each listed serious term to a treatment group is not established by the entries cited. The background therapy is part of the studied regimens, so the results cannot isolate the effect of lersivirine or etravirine from the combination as a whole. These limitations do not negate the posted observations, but they constrain the conclusions that can be drawn from them.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1 — NCT00823979.
• Registry record last updated 2018-12-04; status last verified 2018-11.
• Results first posted 2014-03-14.
• 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

NCT00823979 is a randomized, double-blind, parallel Phase 2b trial marked terminated. It compared lersivirine 750 mg and 1000 mg with etravirine 200 mg, each in combination with darunavir/ritonavir and a nucleos(t)ide reverse transcriptase inhibitor, in antiretroviral-experienced participants with HIV-1 and evidence of NNRTI resistance. The study summary describes a 96 week study, and the primary endpoint was the percentage with HIV-1 RNA below 50 copies/mL at Week 24.

The posted primary percentages were 48.4%, 43.8%, and 67.6% for lersivirine 750 mg, lersivirine 1000 mg, and etravirine, respectively. The comparative risk-difference intervals include zero and are broad. The endpoint uses an intention-to-treat failure rule for specified deaths, discontinuations, loss to follow-up, prohibited antiretroviral changes, and missing Week 24 viral-load data.

The registry record does not report the reason for termination, the original sample-size justification, or several details of the analysis and multiplicity plan. Secondary and serious adverse event results add descriptive context but do not resolve the uncertainty in the primary comparison.