First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants (NCT05163522), a randomized phase 1 study. The primary outcome is Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity.

2. Clinical Question

The central statistical question is descriptive: what adverse-event counts were recorded in the Part 1 single-ascending-dose groups, and how much information do the group sizes provide about those counts? The trial also explored multiple-dose regimens, a drug-drug interaction involving midazolam, and a tablet formulation. These objectives broaden the study’s early development scope, but they do not change the registry’s stated primary endpoint, which is for Part 1.

The record identifies a randomized, double-blind, placebo-controlled study, with the sponsor unblinded. Participants were healthy, and the stated purpose was to assess safety, tolerability and pharmacokinetics of the investigational drug. The registry’s adverse-event counts can describe events reported in the groups, but they do not by themselves answer whether VH4004280 is effective against HIV or establish what would happen in people with HIV.

3. Trial Design

This completed phase 1 study enrolled 73 participants. It began on 2021-12-13 and had a primary completion date of 2023-06-21. The registry describes randomized allocation, double masking, a sequential model and placebo control; the official title specifies that the sponsor was unblinded. Further details of the randomization sequence, allocation ratio and operational meaning of sequential enrollment are not reported in the registry record.

The study had three parts. Part 1 investigated single ascending doses: placebo and VH4004280 doses of 10 mg, 50 mg, 150 mg, 450 mg and 900 mg were administered once orally on Day 1, with follow-up to approximately Day 49. Part 2 investigated multiple ascending doses and a drug-drug interaction. Its placebo and VH4004280 groups received once-daily doses for a 14-day period, with one group receiving 250 mg VH4004280 plus midazolam. That group received single doses of midazolam on days 1, 2 and 15. Follow-up was to approximately Day 63.

Part 3 assessed a single oral dose of the 450 mg tablet formulation, with follow-up to approximately Day 49. The listed interventions were VH4004280, placebo and midazolam. The record does not provide group assignment counts for all enrolled participants as a single design summary, nor does it describe the detailed sequencing rules, dose-escalation decision criteria or pharmacokinetic analysis methods. Those details are not reported in the registry record.

Because the study was an early investigation in healthy participants and used several regimens across parts, its structure is exploratory and descriptive. The primary safety endpoint is specifically attributed to Part 1. Counts for the later parts appear in the adverse-event results as well, but should not be mistaken for a single randomized comparison across all arms.

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.

Only the first 6 of 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the Safety Set which included all enrolled participants in Part 1 (SAD) who received 1 full dose of study treatment. The participants were analyzed according to the treatment they actually received.

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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Number of Participants With Any Adverse Events (AEs) and by Severity, measured over Up to Day 49.

The primary endpoint is the number of participants with any adverse event and by severity in Part 1, through Day 49. An adverse event was defined as an untoward medical occurrence temporally associated with study intervention, whether or not it was considered related to that intervention. This broad definition captures events during the study without requiring the investigator to conclude that the study drug caused them.

Severity was graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric AE. Grade 1 means mild symptoms causing no or minimal interference with usual social and functional activities, with no intervention indicated. Grade 2 means moderate symptoms causing greater than minimal interference, with intervention indicated. Grade 3 means severe symptoms causing inability to perform usual activities, with intervention or hospitalization indicated. Grade 4 means potentially life-threatening symptoms causing inability to perform basic self-care, with intervention indicated to prevent permanent impairment, persistent disability or death. Grade 5 is death.

This endpoint is used in an early safety study because it records the occurrence and graded severity of untoward medical events during exposure and follow-up. It is a participant count, not a rate per unit of time, a measure of pharmacokinetic exposure, or a test of efficacy. The registry describes the primary analysis population as participants in Part 1 who received one full dose, analyzed according to the treatment actually received.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s primary measure is a count of participants with adverse events, classified by severity. A participant count is a binary-outcome summary at the individual level: each participant either meets the event definition for the period or does not. The count does not represent the total number of separate event episodes, and it does not indicate how long each participant was observed beyond the stated follow-up window. The record describes events as any untoward medical occurrence temporally associated with intervention, regardless of whether a relationship to intervention was judged.

What does a count describe?

A count is easiest to interpret alongside the number of participants assessed in that group. It gives the observed frequency of participants meeting the outcome definition in that particular study group. The registry reports participants at risk and participants affected for serious and other adverse events. These are descriptive summaries; no adjusted or unadjusted treatment comparisons are reported in the registry record.

In general, counts from small groups have considerable sampling uncertainty. If the study were repeated with similar participants, event counts could differ even when the underlying risk was unchanged. A confidence interval is a range of values generated by a statistical procedure to convey uncertainty in an estimate. It does not guarantee that the true value lies inside the interval, and it is not a measure of clinical importance. Confidence intervals for the primary endpoint are not reported in the registry record.

How should severity grading be understood?

The endpoint separates severity grades under the Division of AIDS grading table. The grades describe the degree of symptoms and functional interference, and whether intervention, hospitalization or urgent prevention of lasting harm is indicated. Severity is not the same concept as seriousness. In general, severity characterizes intensity, while seriousness is a separate classification based on regulatory criteria and consequences. A serious event need not be assigned the highest severity grade, and a severe event is not automatically classified as serious. The registry’s serious-event counts should therefore be read separately from the endpoint’s severity grading.

The record defines Grade 1 as mild, Grade 2 as moderate, Grade 3 as severe, Grade 4 as potentially life-threatening and Grade 5 as death, with the associated functional and intervention criteria described for each level. The adverse-event results posted for the arms separate serious events and other events, but the reported summaries do not give a full severity-by-grade breakdown. The counts therefore cannot be used to reconstruct how many participants had each grade.

What does the analysis population mean?

The stated primary analysis used the Safety Set: all enrolled participants in Part 1 who received one full dose of study treatment. Participants were analyzed according to the treatment they actually received. This is a safety-oriented population definition. It differs from an intention-to-treat approach that would generally retain participants according to randomized assignment, but the registry does not describe an intention-to-treat analysis for this endpoint. The analysis population for each later-part adverse-event summary is not detailed in the primary endpoint description.

In general, analyzing participants according to treatment received can be useful for describing exposure and safety, but it can make comparisons less directly aligned with randomized assignment if treatment received differs from assignment. Whether that issue occurred in this trial is not reported in the registry record. The Safety Set definition also means the primary endpoint description does not state that every enrolled participant was included; receipt of one full dose was required.

What do the planning calculations mean?

In general, a sample-size calculation estimates how many participants would be needed under specified assumptions to detect a chosen effect with a chosen statistical procedure. Such a calculation is a planning illustration, not a finding from the trial. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. The illustration is not the trial’s own design justification, and its values should not be read as observed power.

For this endpoint, the registry notes that the primary outcome has several categories or time points and was not reduced to one comparison. Thus, a single treatment contrast is not defined by the primary endpoint description. No primary-endpoint sample-size justification, power calculation for the trial design, or prespecified comparison is reported in the registry record. Any planning illustration should be interpreted as conditional on its assumptions, not as evidence about the probability that the trial detected a real effect.

Why might over-dispersion matter?

In general, over-dispersion occurs when variability in observed counts exceeds what a statistical model assumes. It can make standard errors too small and confidence intervals too narrow if the model does not account for the extra variability. That issue is most relevant when modeling event counts or rates, especially when observations vary substantially between participants or groups. The primary endpoint is a participant count, and no count-model analysis or over-dispersion assessment is reported in the registry record. It would therefore be inappropriate to assume that such a model was used.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 27 outcome measures and 0 analyses. It does not describe a multiplicity strategy for handling several outcomes, severity categories, dose groups or study parts. Adjustments for multiple testing, a hierarchy of confirmatory hypotheses and rules for interpreting multiple comparisons are not reported in the registry record. Because no inferential comparisons are listed for the primary endpoint, the posted counts should be treated as descriptive rather than as a set of confirmatory tests.

Missing-data methods are also not reported in the registry record. The primary endpoint population is described as the Part 1 Safety Set, including enrolled participants who received one full dose, analyzed according to treatment actually received. The record does not explain how missing adverse-event information, withdrawals, incomplete follow-up or partially observed records were handled. It does not report whether any participants had incomplete safety follow-up.

The trial is described as randomized and double-blind, with the sponsor unblinded, but details of concealment, who remained masked, and any assessment of masking are not reported in the registry record. Interim analyses, stopping rules and a detailed statistical analysis plan are not reported either. These omissions do not show that the procedures were absent; they mean the registry record does not provide enough information to assess them. Conclusions should remain limited to the reported participant counts and the stated analysis population.

11. 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 serious-adverse-event figures are participant counts, not totals of event episodes. For every listed group across Parts 1, 2 and 3, the registry reports 0 participants with serious adverse events. It also reports 0 deaths in every group. Each group’s at-risk count is shown with its event count, which helps readers see the denominator behind the observation.

A zero count means no such event was recorded among the participants at risk during the relevant observation period. In general, it does not prove that the underlying risk is zero, particularly when groups are small. The different parts also had different regimens and follow-up durations, so their counts should not be combined into an unadjusted overall comparison. The registry record does not give serious-event confidence intervals or formal between-group tests.

Seriousness should not be confused with the severity grades used in the primary endpoint. The grade definitions describe symptoms and functional impact, while serious-event classification is separate. The registry’s zero serious-event counts do not provide a full breakdown of the severity grades of other reported adverse events.

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

The posted results describe adverse events recorded in a small early-phase study of healthy participants exposed to several VH4004280 regimens. The Part 1 primary endpoint counts participants with any adverse event by severity, and the registry also reports serious and other adverse-event counts for groups in the later parts. Across the listed groups, no serious adverse events or deaths were recorded. Other-adverse-event counts varied among groups, including groups with no participants affected and groups with several participants affected.

These observations are useful as a description of what was recorded under the studied conditions. They provide information from single-dose, multiple-dose, drug-drug interaction and tablet-formulation settings. The record’s safety population is defined by receipt of one full dose in Part 1 and analysis by treatment received. The counts should therefore be interpreted within those study conditions and the specified follow-up, rather than as estimates that necessarily apply to other populations or use settings.

The results do not establish that VH4004280 is effective against HIV, and the primary endpoint does not measure antiviral activity. They do not establish that a regimen is free of risk: a zero serious-event count in a small group cannot exclude uncommon events. The counts also do not establish that one dose is safer than another, because no inferential comparison is reported and the study parts are not all direct comparisons.

In general, a randomized design can support fair comparisons when the comparison, analysis population and statistical methods are specified and followed. The registry record does not report a primary inferential contrast or a statistical analysis for these safety counts. The results are therefore best read as descriptive evidence from an early clinical investigation, not as a definitive comparative safety assessment. They also do not replace information from larger or longer studies, whose results are not reported in this registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable because the primary endpoint is a participant-level safety count in a first-in-human investigation, rather than an efficacy outcome. The study spans single ascending doses, multiple ascending doses, a drug-drug interaction and a tablet formulation. That breadth creates several distinct descriptive contexts, but it also means the listed groups are not all interchangeable arms in one simple comparison.

Small group sizes make the distinction between observed counts and underlying event probabilities especially important. A count of zero is a real observation for the participants followed, but it does not show that an event is impossible. Counts of other adverse events can be described group by group, while strong claims about differences require a defined contrast, a suitable analysis and an assessment of uncertainty. The registry lists no analyses for the outcomes.

The study also illustrates why endpoints need precise definitions. Any adverse event includes an untoward medical occurrence whether or not it is considered related to intervention. Severity grading and serious-event classification are distinct ways of characterizing safety, and they answer different questions. Keeping those classifications separate prevents a serious-event count from being mistaken for a complete severity profile.

Finally, the analysis population matters. The primary safety population includes Part 1 participants who received one full dose and uses treatment actually received. That definition is tailored to describing exposure and safety, but it should be considered when interpreting counts alongside randomized assignment. The record’s limits on statistical analysis and missing-data details leave the reader with a useful descriptive account, while also showing why registry counts alone cannot resolve broader comparative or rare-event questions.

14. 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 endpoint covers Part 1 and follow-up up to Day 49, while the other listed parts have different regimens and follow-up to approximately Day 63 or Day 49. This variation limits direct comparison across parts. One group received both VH4004280 and midazolam, so its adverse-event counts cannot be attributed to VH4004280 alone from the registry summary. The tablet group also represents a separate formulation and study part.

The group sizes reported for adverse events are small, and the registry does not provide confidence intervals or inferential comparisons for the counts. Zero serious events and zero deaths are therefore descriptive observations, not proof that such events cannot occur. The other-event summaries do not give detailed event terms or a complete severity-by-grade breakdown in the information reported for this endpoint.

The primary endpoint population is defined as participants in Part 1 who received one full dose, analyzed by treatment actually received. The registry does not report how missing data, withdrawals or incomplete follow-up were handled, or give corresponding analysis-population details for every later part. It also does not report the detailed statistical analysis plan, multiplicity procedures, interim analyses or a trial-specific sample-size justification. These limitations concern what can be learned from the registry record and do not establish whether additional procedures or information exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants — NCT05163522.
• Registry record last updated 2025-07-30; status last verified 2025-07.
• Results first posted 2025-07-30.
• 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.

18. Record Summary

NCT05163522 is a completed phase 1, randomized, double-blind, placebo-controlled study of oral VH4004280 in healthy participants. The record describes a sequential study with sponsor unblinded. It enrolled 73 participants and began on 2021-12-13, with primary completion on 2023-06-21.

The study included single ascending doses, multiple ascending doses with a midazolam interaction group, and a single-dose tablet formulation group. The primary endpoint counted Part 1 participants with adverse events by severity through Day 49. The Part 1 Safety Set included enrolled participants who received one full dose and were analyzed according to treatment received.

The registry reports 27 outcome measures and 0 analyses. Serious adverse events and deaths were recorded as 0 in each listed group; other-adverse-event counts varied by group. The record does not report inferential comparisons, confidence intervals or detailed methods for missing data and multiplicity.