Doravirine/Islatravir (DOR/ISL) in Heavily Treatment-Experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Doravirine/Islatravir (DOR/ISL) in Heavily Treatment-Experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019) (NCT04233216), a randomized phase 3 study. The primary outcome is Percentage of Participants Receiving Doravirine/Islatravir (DOR/ISL) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 in Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Compared to Placebo Treatment.

2. Clinical Question

3. Trial Design

NCT04233216 is described as a phase 3, randomized, double-masked, parallel-group clinical study. The registry lists an enrollment of 35 and a completed study status. The recorded study dates are 2020-03-18 for the start and 2022-11-21 for primary completion. The sponsor is Merck Sharp & Dohme LLC.

The study had two parts and evaluated ISL, DOR, and the fixed-dose combination DOR/ISL in heavily treatment-experienced participants with HIV-1 infection. The brief description frames the initial comparison as each active treatment versus placebo, with the assigned treatment added to failing ART. The primary outcome considered only the DOR/ISL and placebo groups. The listed primary-analysis counts are 7 participants for each of those groups; the ISL and DOR groups have no primary endpoint values reported in this record.

In the regimen descriptions, the assigned initial treatment was taken from Day 1 to Day 7. From Day 8 to Week 97, the described treatment was open-label DOR/ISL with OBT. Thus, the initial randomized period and the longer open-label treatment period address different study contexts. The Day 8 endpoint concerns the short initial period, not the later open-label period.

Randomization is intended, in general, to make treatment groups comparable on average at the start of a study. Masking is intended, in general, to reduce the influence of treatment knowledge on participants or study conduct. Those design features do not eliminate uncertainty, especially when the primary groups are small, and the registry record does not provide further details about implementation of randomization or masking. It also does not report the rationale for the enrollment target or a sample-size justification.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received at least 1 dose of study intervention based on the treatment group to which they were randomized and had baseline data for those analyses that require baseline data.

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 Percentage of Participants Receiving Doravirine/Islatravir (DOR/ISL) With ≥0.5 log10 Change From Day 1 Baseline to Day 8 in Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Compared to Placebo Treatment, measured over Day 1 (baseline) and Day 8.

The primary endpoint is the percentage of participants whose HIV-1 RNA decreased by at least 0.5 log10 from the Day 1 baseline to Day 8. The registry says the central laboratory identified qualifying decreases using an Abbott Real Time Polymerase Chain Reaction assay, with a lower limit of detection of 40 copies/mL. Only participants in the DOR/ISL FDC and placebo groups were analyzed for this outcome.

This endpoint converts a measured change in viral RNA into a binary outcome: each analyzed participant either met the stated reduction threshold or did not. The percentage describes how common that threshold response was in each group. As a general statistical point, a threshold endpoint can make a result easier to interpret as a proportion of participants meeting a defined criterion, but it does not show the full range of individual RNA changes. Participants just short of the threshold and those with little or no change are grouped together as not meeting it, while the magnitude of change among those meeting it is not conveyed by the percentage alone.

The endpoint is assessed at Day 8 relative to Day 1. It therefore describes an early response and should not be treated as a measure of the longer open-label period through Week 97. The registry also lists continuous mean-change and other threshold outcomes among secondary outcomes, but their results are not included in the record analyzed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the percentage represent?

The endpoint is a binary outcome, meaning each participant is classified according to whether the measured HIV-1 RNA decrease reached the stated threshold. The reported percentage is the proportion of analyzed participants who met that criterion in a treatment group. The registry identifies the qualifying change as at least 0.5 log10 from Day 1 baseline to Day 8. This percentage does not represent the average change in RNA and does not retain the detailed measurements for participants who did or did not cross the threshold.

As a general explanation, binary outcomes are often summarized with counts and proportions because these directly describe how many participants experienced the defined event. With small groups, each participant represents a substantial part of the group’s observed result. That makes estimates sensitive to the outcome of an individual participant and can produce considerable statistical uncertainty. Here, each primary group contains 7 participants, so the percentages should be read alongside their confidence intervals rather than as exact estimates of the underlying response proportions.

How should the confidence intervals be read?

The registry presents a 95% confidence interval for each group’s percentage. For DOR/ISL, the reported estimate is 85.7% with an interval from 42.1% to 99.6%; for placebo, it is 0.0% with an interval from 0.0% to 41.0%. In general, an interval communicates the range of uncertainty associated with an estimate under the statistical method used. Wider intervals indicate less precision than narrower intervals. The registry record does not identify the specific interval-construction method, so the method should not be inferred from the displayed bounds.

These are intervals for the separate group percentages. A treatment comparison is more directly represented by an estimated difference or another contrast between groups, accompanied by its uncertainty and, when applicable, a test result. The registry record does not report those quantities for the primary endpoint. A reader should therefore distinguish the descriptive group estimates from a formal comparison result.

What does randomization contribute?

As a general statistical concept, random assignment aims to create treatment groups that are comparable in expectation, including with respect to measured and unmeasured characteristics. It supports interpretation of a between-group contrast as an effect of assignment when the analysis and follow-up preserve the benefits of randomization. However, randomization does not ensure that small groups will have identical characteristics, and the registry record does not describe the baseline characteristics needed to assess balance in these groups. It also does not describe the allocation procedure or any stratification factors.

The study is listed as double-masked, but the record does not explain which parties were masked, how masking was maintained, or whether it was assessed. In general, masking can limit the influence of knowledge about assigned treatment on behavior, reporting, or assessment. It cannot remove uncertainty due to a small number of participants or missing outcome data.

What is not reported about the analysis?

The registry defines the primary analysis population as randomized participants who received at least 1 dose of study intervention and had baseline data for analyses requiring baseline data. This is a treatment-group-based population definition, with assignment retained as the basis for grouping. The record does not give a separate account of how participants with missing Day 8 measurements were handled, whether any imputation was used, or whether additional analysis populations were examined.

The record also does not report the statistical model or test used for the primary comparison, an adjusted effect estimate, a standard error, or a direct confidence interval for the between-group contrast. The confidence intervals shown for the arm percentages should not be treated as if they were results from an unreported model. The statistical analysis plan, any interim analyses, and any sample-size justification are not reported in the registry record.

How do the study periods shape interpretation?

The randomized initial treatment period runs from Day 1 to Day 7 in the regimen descriptions, and the primary outcome compares Day 1 baseline with Day 8. The regimen descriptions then specify open-label DOR/ISL with OBT from Day 8 to Week 97. As a general design principle, outcomes measured during a randomized comparison and outcomes measured during a later open-label period answer different questions. The Day 8 result is tied to the initial randomized treatment assignment; it should not be extended to the subsequent period without relevant results and an appropriate analysis.

The registry lists several types of secondary outcomes, including threshold-based and mean changes in HIV-1 RNA, adverse events, and discontinuation due to adverse events. The statistical methods for those outcomes, including any adjustments for multiple comparisons, are not reported in the registry record. No sample-size planning illustrations or calculations should be interpreted as observed power; the record does not state the trial’s own design justification.

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("DOR/ISL + ART", "Placebo + ART")
n      <- c(7, 7)
events <- c(6, 0)
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  DOR/ISL + ART  7  6  85.7  42.1  99.6  48.7  97.4  47.3  96.8
ARM  Placebo + ART  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint focused on the percentage meeting the Day 8 HIV-1 RNA reduction threshold in the DOR/ISL and placebo groups. It also lists secondary outcomes involving adverse events, discontinuation, other RNA-change thresholds, and mean RNA change. A study that examines multiple outcomes or multiple treatment comparisons raises a general statistical issue: the chance of at least one apparently notable result can increase as the number of tests increases. Methods for controlling or otherwise addressing this issue depend on the prespecified analysis plan.

The registry record does not report a multiplicity strategy, the ordering or hierarchy of tests, or which secondary comparisons were confirmatory. It also does not report interim analyses or stopping rules. The listed outcomes should therefore not be assumed to have been tested under a particular adjustment or testing sequence.

The primary population is described as randomized participants who received at least 1 dose of study intervention and had baseline data for analyses that require it. The registry record does not report the number of participants with missing Day 8 measurements, the reasons for missingness, how missing endpoint data were handled, or whether sensitivity analyses were conducted. Those details matter because the observed percentages describe participants included in the analysis, and missing outcomes can affect how representative that group is of all randomized participants.

The record does not report a full statistical analysis plan, a sample-size justification, or a direct inferential comparison for the primary endpoint. The results should consequently be interpreted as posted group estimates with their confidence intervals, not as a complete account of the planned inferential framework. General statistical methods cannot fill in these unreported design and analysis details.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: angina pectoris (14.3%), colitis ulcerative (14.3%), covid-19 pneumonia (14.3%), sars-cov-2 sepsis (14.3%), lower limb fracture (14.3%).

The registry lists serious adverse event counts by group, alongside the number at risk. The counts are 2 of 7 for ISL+ART, 2 of 14 for DOR+ART, 0 of 7 for DOR/ISL+ART, and 2 of 7 for Placebo+ART. These are counts of participants with serious adverse events, not counts of every serious event that occurred. No deaths are listed in any of the four groups.

The registry also reports several serious adverse event terms at 14.3% each: angina pectoris, colitis ulcerative, COVID-19 pneumonia, SARS-CoV-2 sepsis, lower limb fracture, and reactive gastropathy. The record does not establish from these term listings that an event was caused by a study treatment. The terms should be read as reported safety information, not as proof of treatment attribution.

As a general statistical point, safety counts in small groups can be unstable, and an absence of a recorded event in a group does not establish that an event cannot occur. These figures also do not provide a randomized comparison adjusted for follow-up or other factors. The registry record does not provide further details about event timing, severity beyond the serious classification, or causality assessments. Safety counts should be considered separately from the Day 8 primary efficacy endpoint.

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

The primary results describe the proportion of analyzed participants who met a defined early HIV-1 RNA reduction threshold. The registry reports 85.7% among 7 participants assigned to DOR/ISL and 0.0% among 7 assigned to placebo, with respective 95% confidence intervals of 42.1% to 99.6% and 0.0% to 41.0%. This is a descriptive contrast between the reported group percentages.

The result does not, by itself, provide a formal estimate of the difference between groups or its confidence interval. A direct contrast would quantify the comparative estimate and its uncertainty using a specified analysis. The registry record does not report that result or a p value. The group percentages therefore should not be recast as proof of a statistically significant or nonsignificant treatment effect.

The endpoint is limited to change from Day 1 baseline to Day 8. It does not describe the full distribution of RNA changes, the mean change, longer-term outcomes through Week 97, or the results of the separate ISL and DOR groups. The registry’s regimen descriptions indicate that participants moved to open-label DOR/ISL with OBT from Day 8 onward, so outcomes from that later period would address a different treatment context.

The reported percentages also do not establish safety, tolerability, or clinical benefit. The registry lists adverse event outcomes separately, and the serious event counts are descriptive. No causal conclusions about adverse events follow from the counts alone. General interpretation of any treatment comparison requires attention to design, analysis population, missing data, uncertainty, and the endpoint actually measured.

In short, the posted primary figures show that the threshold was met by a larger observed share of the DOR/ISL group than the placebo group in this small Day 8 comparison. The estimates are imprecise, and the registry record does not include the formal comparative analysis needed to quantify the difference statistically. The findings should remain bounded to this endpoint and comparison.

14. Why This Trial Matters Statistically

This trial raises several important statistical reading questions. The primary endpoint is a threshold-based binary measure, while the biological measurement underlying it is continuous. That distinction matters: a percentage meeting a threshold communicates the frequency of a defined response, but it can conceal variation in the size of the RNA changes and in observations close to the cutoff. The registry separately lists mean-change and additional threshold outcomes, emphasizing that different summaries can address different aspects of the data.

The primary comparison includes 7 participants per group. Small groups make percentage estimates sensitive to individual outcomes and leave substantial uncertainty, as reflected in the reported confidence intervals. A point estimate can look precise because it is written as a percentage, but the interval shows that the underlying response proportion is much less precisely determined. Reporting the confidence intervals alongside the percentages is therefore essential to interpretation.

The study also illustrates the importance of separating a descriptive comparison from a formal inferential result. Separate arm estimates do not themselves provide a confidence interval or test for the difference between arms. The registry record does not report a direct comparative estimate or p value, so the result cannot be fully characterized using those inferential quantities.

Finally, the trial’s timing matters. The primary endpoint evaluates an early change from Day 1 to Day 8 during the initial assigned-treatment period, whereas the regimen descriptions specify open-label DOR/ISL from Day 8 to Week 97. Statistical conclusions must track the particular period, population, and endpoint being analyzed. This helps prevent an early biomarker response from being mistaken for a result about later outcomes or the other treatment groups.

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 primary comparison is based on 7 participants in each of the DOR/ISL and placebo groups. The estimates have broad confidence intervals, so the observed percentages do not pin down the underlying group response proportions with high precision. The overall enrollment was 35, but the primary endpoint figures concern only the two groups analyzed for that outcome. No primary values are reported for the ISL or DOR groups.

The primary endpoint is a binary threshold response measured from Day 1 to Day 8. It does not show the distribution of individual RNA changes or establish the size of an average change. It also does not characterize longer-term outcomes during the open-label period described through Week 97. The registry lists other endpoints, but their result values are not included in the record analyzed.

The registry record does not report a direct treatment contrast, its confidence interval, or a p value for the primary outcome. It does not report the statistical model, missing-data handling, multiplicity procedure, sample-size justification, or interim analyses. These omissions limit assessment of the planned inferential framework and the sensitivity of results to missing observations or multiple testing.

Additional details about baseline comparability, the implementation of masking and randomization, and the timing and attribution of adverse events are not reported in the registry record. The serious adverse event counts are descriptive and do not alone establish causation. These limitations do not negate the posted observations, but they constrain how far those observations can be generalized or interpreted as comparative evidence.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Doravirine/Islatravir (DOR/ISL) in Heavily Treatment-Experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019) — NCT04233216.
• Registry record last updated 2024-12-27; status last verified 2024-12.
• Results first posted 2023-12-08.
• 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

NCT04233216 is a completed, randomized, double-masked, parallel-group phase 3 study of ISL, DOR, and DOR/ISL in heavily treatment-experienced participants with HIV-1 infection. The registry lists an enrollment of 35. The study began on 2020-03-18 and reached primary completion on 2022-11-21; the sponsor is Merck Sharp & Dohme LLC.

The primary endpoint was the percentage with at least a 0.5 log10 decrease in HIV-1 RNA from Day 1 baseline to Day 8. The DOR/ISL group had 7 participants and a reported percentage of 85.7% (95% CI 42.1% to 99.6%); the placebo group had 7 participants and a reported percentage of 0.0% (95% CI 0.0% to 41.0%). A formal between-group estimate and p value are not reported in the registry record. Serious adverse event and other outcome information should be interpreted as descriptive unless accompanied by the relevant comparative analysis.