Drug-Drug Interaction Study of Vesatolimod in Adults With HIV-1 Who Have Very Low or Undetectable Virus Levels: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-Drug Interaction Study of Vesatolimod in Adults With HIV-1 Who Have Very Low or Undetectable Virus Levels (NCT05458102), a non-randomized phase 1 study. The primary outcome is Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES).

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, non-randomized, parallel study of vesatolimod pharmacokinetics in virologically suppressed adults with HIV-1 receiving antiretroviral therapy. The registry lists enrollment as 18 and the study status as terminated. It records a start date of 2022-08-19 and a primary completion date of 2023-05-01. The reason for termination is not reported in the registry record.

The study had two cohorts. Cohort 1 evaluated vesatolimod with cobicistat and voriconazole. Its description includes a single dose of vesatolimod 2 mg in Period 1, cobicistat 150 mg once daily in Period 2 with a single vesatolimod dose, and a voriconazole period. The registry text available for the voriconazole period is incomplete, so the complete schedule is not reported in the registry record. Cohort 2 evaluated vesatolimod with rifabutin. The record describes vesatolimod 6 mg alone in Period 1, followed by rifabutin 300 mg once daily in Period 2 with a vesatolimod dose. It also describes a washout period of 7 to 14 days between the specified treatment starts.

Because treatment allocation was non-randomized and the design was open-label, the study does not provide a randomized, blinded comparison. Its stated focus is pharmacokinetics: whether medicines that inhibit or induce drug-metabolizing enzymes or transporters alter vesatolimod exposure. The registry reports 13 outcome measures and 10 analyses, but the analysis methods beyond the outcome descriptions are not reported in the registry record. The extent to which the planned cohort schedules were completed is also not reported in the registry record.

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: 59 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The VES PK Analysis Set included participants who received at least 1 dose of VES and had at least 1 nonmissing PK concentration value.

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: The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES), measured over Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6.

The primary endpoint is vesatolimod AUClast, expressed in h*pg/mL. It is defined as the area under the concentration-versus-time curve from time zero to the last quantifiable concentration. Concentrations were scheduled for measurement before dosing and at multiple post-dose times through 96 hours, with the specific period and day differing by cohort. The endpoint summarizes drug exposure across the observed concentration profile rather than representing a single concentration measurement.

Pharmacokinetic exposure measures are used to describe how much drug is present over time. In a drug-interaction study, comparing exposure under different medicine conditions can help characterize whether a co-administered medicine is associated with altered drug concentrations. AUClast uses the observed concentration profile up to the final quantifiable measurement; it does not, by itself, describe concentrations after that point or establish why any difference occurred.

The registry specifies the mean as the summary parameter and standard deviation as the dispersion measure. These describe the average AUClast and the spread of values around that average in the analysis set. However, no AUClast means, standard deviations, treatment contrasts, or confidence intervals are reported in the registry record. Consequently, the direction, magnitude, and precision of the primary endpoint findings cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does AUClast represent?

AUClast is a continuous pharmacokinetic measure based on concentrations measured over time. The area under a concentration-versus-time curve summarizes exposure from time zero through the last quantifiable concentration. In general, this kind of measure uses information across multiple observations rather than relying on one concentration at one time. The endpoint is limited to the observed period ending at the last quantifiable value; it is not a measure of exposure beyond that observation.

The registry specifies the mean and standard deviation for the primary outcome. In general, the mean describes the center of a set of measurements, and the standard deviation describes their spread around that mean. Both are useful for understanding a continuous outcome, but they do not by themselves show the uncertainty in a comparison between treatment conditions. Confidence intervals for treatment contrasts would help communicate that uncertainty; such estimates are not reported in the registry record.

How should a drug-interaction comparison be understood?

In general, a drug-interaction study asks whether exposure to one medicine differs when another medicine is present. Cobicistat and voriconazole are described as CYP3A inhibitors, and cobicistat is also described as affecting P-gp and BCRP. Rifabutin is described as a moderate CYP3A inducer. These descriptions provide the study's pharmacological rationale, but they do not establish that any particular interaction occurred. The primary endpoint results needed to assess exposure changes are not reported.

The study is non-randomized and open-label. In general, randomization helps balance measured and unmeasured characteristics across comparison groups, while blinding can reduce the influence of knowledge of treatment assignment on some aspects of a study. Neither feature is reported for this trial: the registry lists non-randomized allocation and no masking. The design therefore should not be described as a randomized, blinded comparison. The registry does not report whether analyses accounted for period, sequence, or participant-level structure, so those methods should not be assumed.

What do the sampling schedule and analysis population tell readers?

Concentrations were scheduled before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after dosing. The relevant period and day differ between cohorts. In general, sampling at multiple times makes it possible to characterize the concentration profile and derive exposure measures. The actual number of measurements available for each participant, and how missing or nonquantifiable concentrations were handled, are not reported in the registry record.

The VES PK Analysis Set includes participants who received at least one dose of vesatolimod and had at least one nonmissing pharmacokinetic concentration value. This definition identifies who could contribute to the pharmacokinetic analysis, but it does not indicate how many participants met the criteria. It also does not specify whether every participant in that set contributed to every treatment-period estimate. The number analyzed for each endpoint and any exclusions are not reported in the registry record.

What do planning illustrations mean?

In general, a sample-size illustration uses assumptions about the target effect, variability, significance level, allocation, and statistical model to show how a future study might be planned. The stated illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Their target effect is expressed as a stated fraction of the observed effect. Such planning quantities are hypothetical, not observed trial outcomes, and they are not “observed power.” The registry does not report the trial's own sample-size justification or establish that these assumptions governed its design.

The record notes that participant counts per arm are used for non-time-to-event illustrations, whereas time-to-event illustrations use total events. This study's primary outcome is continuous, so the meaning of a planning illustration depends on the specific assumptions attached to it. No planning values or underlying observed AUClast effect estimates are reported in the registry record, so no numerical planning conclusion can be drawn from the available endpoint information.

What analysis details remain unknown?

The registry lists 10 analyses and 13 outcome measures, but it does not report a detailed statistical analysis plan, model specification, confidence-interval method, or handling of multiple comparisons. It also does not report an interim-analysis plan, a sample-size justification, or a method for managing missing pharmacokinetic data. General statistical practice cannot fill these trial-specific gaps. Those details would be needed to evaluate whether estimates were adjusted for the study structure, how uncertainty was quantified, and how the several treatment conditions and outcomes were handled together.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort 1: Vesatolimod 2 mg", "Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg", "Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg", "Cohort 2: Vesatolimod 6 mg", "Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg")
n   <- c(15, 13, 11, 2, 2)
m   <- c(13500, 61900, 14600, 16400, 86300)
sp  <- c(9500, 35400, 11000, 17900, 16000)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort 1: Vesatolimod 2 mg  15  13500.000  9500.000  8239.075  18760.925
CARM  Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg  13  61900.000  35400.000  40507.994  83292.006
CARM  Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg  11  14600.000  11000.000  7210.099  21989.901
CARM  Cohort 2: Vesatolimod 6 mg  2  16400.000  17900.000  -144425.119  177225.119
CARM  Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg  2  86300.000  16000.000  -57454.297  230054.297

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 10 analyses. It does not report how the analyses were organized into primary and secondary families for statistical testing, whether a multiplicity adjustment was planned, or how any adjustment was applied. When multiple outcomes or treatment comparisons are examined, the chance of at least one apparently unusual finding can increase; in general, multiplicity methods address that issue. Without the registry's analysis plan and reported results, it is not possible to determine whether multiplicity was considered or how it affects interpretation.

The primary pharmacokinetic analysis set is defined as participants who received at least one dose of vesatolimod and had at least one nonmissing pharmacokinetic concentration value. This clarifies a basic eligibility condition for analysis, but the number included in each endpoint analysis is not reported in the registry record. The record also does not describe how missing concentration measurements, concentrations below quantification, or incomplete profiles were handled. The endpoint definition refers to the last quantifiable concentration, but that definition alone does not explain the rules used when values were missing or unquantifiable.

Other analysis populations, such as a safety population definition, are not reported in the registry record. No imputation method, sensitivity analysis for missing data, or assessment of the consequences of missingness is reported. The reason for termination is also not reported, so its relationship to recruitment, treatment completion, and analysis completeness cannot be assessed. These omissions limit assessment of potential bias and of how robust the reported safety and pharmacokinetic summaries are.

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 non-serious adverse event terms

The registry reports serious adverse events by treatment group. The serious adverse event count is 0 in each listed group, including groups with vesatolimod alone, the interacting medicines alone, and the combinations. Deaths are also reported as 0 in each listed group. These are descriptive counts for the group-specific numbers at risk; they should not be interpreted as proof that serious events or deaths are impossible.

Other adverse events are reported in some groups. The registry lists 2 among 15 at risk for Cohort 1 vesatolimod 2 mg, 5 among 13 at risk for Cohort 1 cobicistat 150 mg, none among 13 at risk for the Cohort 1 vesatolimod and cobicistat combination, 4 among 11 at risk for Cohort 1 voriconazole 400 mg, and 1 among 11 at risk in each of the Cohort 1 voriconazole 200 mg and vesatolimod plus voriconazole groups. In Cohort 2, the count is 0 among 2 at risk for vesatolimod 6 mg and 1 among 2 at risk in each rifabutin-containing group.

These counts do not establish that treatment caused an event or that groups differ in risk. Group sizes are small, the allocation was non-randomized, and event descriptions and comparative safety analyses are not reported in the registry record. The no-treatment group lists zero at risk, so it does not provide a safety comparison.

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

The study addresses a pharmacokinetic question: whether cobicistat, voriconazole, or rifabutin affects vesatolimod exposure in adults with HIV-1 receiving antiretroviral therapy. The registry identifies AUClast as the primary measure and describes the treatment periods and concentration-sampling schedule. This establishes what the study set out to measure, but the primary endpoint values are not reported in the registry record.

Without reported means, standard deviations, treatment contrasts, or confidence intervals, readers cannot determine the direction or magnitude of any exposure difference or its precision. The missing result must not be interpreted as evidence of no interaction. The registry's terminated status also does not reveal whether the study stopped early, why it stopped, or whether that affected the primary analysis; the reason is not reported in the registry record.

The non-randomized, open-label design is important context. In general, comparisons from non-randomized groups can be affected by differences between treatment conditions or by the way participants enter those conditions. The registry does not provide enough analytic detail to assess how such issues were handled. The study should therefore be described by its stated design and available descriptive data, without claiming that it establishes a causal effect.

The adverse event counts offer a limited descriptive account of safety in the listed treatment groups. No serious adverse events or deaths are reported in those groups, while other adverse events appear in some groups. The counts do not establish comparative safety, and they do not answer the pharmacokinetic question. Overall, the registry record describes the question, design, endpoint definition, analysis-set criterion, and safety counts, but does not report the primary pharmacokinetic results needed to assess the study's central objective.

14. Why This Trial Matters Statistically

Drug-interaction studies are statistically useful because they ask a focused question about exposure under different medicine conditions. A concentration-time endpoint such as AUClast can summarize information across a profile and is directly aligned with a pharmacokinetic objective. The registry also identifies interacting medicines with different stated effects on CYP3A or drug transport, making the treatment conditions relevant to the study's stated question.

At the same time, this record illustrates why a clearly named endpoint is not enough to evaluate a study's findings. The registry defines AUClast, its unit, the summary measure, the dispersion measure, and the analysis-set criterion, but does not report the endpoint estimates or their uncertainty. Without those results, readers cannot assess the observed exposure patterns or distinguish a precise estimate from an uncertain one.

The design also matters for statistical interpretation. Non-randomized allocation and open-label conduct differ from randomized, blinded comparison, and the record does not report analytic methods that would clarify how treatment-period comparisons were handled. The safety counts are similarly descriptive and arise from small, varied group sizes. They should not be treated as comparative estimates.

Finally, a terminated study with an unreported reason and missing primary endpoint results underscores the importance of complete reporting. The registry's available information supports a careful account of the question and methods, but not a conclusion about the magnitude of a drug interaction. Stating that boundary is part of sound statistical interpretation: definitions and design features can be described, while unreported outcomes remain unknown.

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 limitation for interpreting the central research question is that AUClast results are not reported in the registry record. Means, standard deviations, comparative estimates, and confidence intervals are absent. Thus, the direction, magnitude, and precision of vesatolimod exposure differences cannot be evaluated. The record's terminated status adds uncertainty because the reason for termination and its consequences for the planned analyses are not reported.

The study is non-randomized and open-label. This limits the basis for interpreting treatment-period comparisons as causal, and the registry does not describe adjustments for potential differences between conditions. Although the design is labeled parallel, the arm descriptions also specify treatment periods; the statistical handling of period and participant structure is not reported. The cohort 1 treatment description for the voriconazole period is incomplete in the registry record, limiting a full account of that schedule.

The analysis-set definition requires at least one vesatolimod dose and one nonmissing pharmacokinetic concentration, but the number analyzed for each comparison is not reported. Missing-data rules, handling of nonquantifiable values, and sensitivity analyses are not reported. The registry lists multiple outcomes and analyses without explaining the multiplicity strategy. The sample-size justification, interim-analysis plan, and detailed statistical model are likewise not reported in the registry record.

Safety reporting is limited to group counts for serious and other adverse events and deaths. Event-level descriptions and comparative analyses are not reported. The small and unequal group-specific numbers at risk, together with non-randomized allocation, make these counts descriptive rather than a basis for firm comparisons.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Drug-Drug Interaction Study of Vesatolimod in Adults With HIV-1 Who Have Very Low or Undetectable Virus Levels — NCT05458102.
• Registry record last updated 2024-12-03; status last verified 2024-10.
• Results first posted 2024-12-03.
• 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

NCT05458102 is a phase 1, open-label, non-randomized study of vesatolimod pharmacokinetics in virologically suppressed adults with HIV-1 receiving antiretroviral therapy. The study examined cobicistat, voriconazole, and rifabutin in separate cohorts and treatment periods. The registry lists enrollment of 18, status as terminated, and a primary endpoint of vesatolimod AUClast.

AUClast is defined as the area under the concentration-versus-time curve from time zero to the last quantifiable concentration. The pharmacokinetic analysis set includes participants with at least one vesatolimod dose and at least one nonmissing pharmacokinetic concentration. The primary endpoint estimates and the reason for termination are not reported in the registry record. Serious adverse events and deaths are listed as 0 in all reported treatment groups; other adverse event counts vary by group. The registry does not report a detailed statistical analysis plan or multiplicity and missing-data methods.