Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity (NCT05492318), a na phase 1 study. The primary outcome is Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug.

2. Clinical Question

The study focused on drug-drug interaction potential, rather than on a clinical treatment outcome. Its primary objective was to assess potential inhibitory and inducing effects of oral givinostat on the single-dose pharmacokinetics of intravenous or oral midazolam and oral dabigatran etexilate. The secondary objective was to assess the safety and tolerability of concomitant administration of givinostat with midazolam and dabigatran etexilate.

For midazolam, the endpoint description sets out within-study comparisons: single-dose administration without givinostat and co-administration during periods intended to assess potential inhibitory or inducing effects. The registry record identifies the midazolam measurements and timing, but does not report the numerical concentrations, geometric means, confidence intervals, or effect estimates needed to describe the size or direction of any change. The objective is therefore clear, while the posted record does not establish the observed pharmacokinetic result.

The dabigatran question is also stated as a potential interaction assessment. However, the primary endpoint details posted in the registry record concern Cmax for midazolam and 1-hydroxymidazolam. Numerical dabigatran endpoint results and their precision are not reported in the registry record.

3. Trial Design

This was a phase 1, open-label, single-center study in healthy subjects. The registry lists the study as completed, with a start date of 2022-03-21 and a primary completion date of 2022-05-08. Enrollment was 26. Allocation is recorded as not applicable, masking as none, and the model as single group. These design features matter: the study was not a randomized, masked comparison of separate groups receiving different treatments.

The study examined pharmacokinetic measurements under different dosing conditions. The primary endpoint description identifies intravenous midazolam alone on Day 1, with intravenous midazolam and givinostat on Day 6 for potential inhibition and Day 17 for potential induction. For oral midazolam, it identifies administration alone on Day 2 and co-administration with givinostat on Day 7 for potential inhibition and Day 18 for potential induction. The record also describes single doses of intravenous midazolam 1 mg and dabigatran etexilate 75 mg, and oral midazolam 2.5 mg. The listed dabigatran product was an oral hard capsule.

The detailed dosing description is incomplete in the registry record, including the text describing the timing of oral midazolam. It is therefore not possible to reconstruct the full administration schedule or the complete givinostat dosing regimen from the record. The listed givinostat product concentration, 10 mg/mL, does not by itself establish the administered dose.

Blood sampling for intravenous midazolam was described as occurring before dosing and at specified post-dose times through 24 hours on Days 1, 6, and 17. For oral midazolam, samples were described at specified post-dose times through 24 hours on Days 2, 7, and 18. The record states that samples were used to determine plasma concentrations of midazolam and 1-hydroxymidazolam.

A single-group, repeated-condition design can support within-study pharmacokinetic comparisons, but it is not equivalent to a randomized parallel-group comparison. Open-label conduct means treatment assignment was not masked. The registry record does not report the sequence-generation method, a washout interval, or other details needed to assess the full conduct of the dosing sequence. Those details are 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.

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: Pharmacokinetic Analysis Population:Twenty-six (26) subjects were enrolled in Part 1 of the study and provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.

6. Primary Endpoint

The registry lists the primary outcome as Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug, measured over In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18..

The primary endpoint is maximum observed plasma concentration, or Cmax, for midazolam and its metabolite 1-hydroxymidazolam after single doses of the parent drug. The registry specifies geometric means and 95% confidence intervals as the summary and measure of dispersion, with concentrations expressed in pg/mL. Measurements were intended to be obtained over the 24 hours after intravenous or oral midazolam administration under the study conditions described in the record.

As a general pharmacokinetic concept, Cmax describes the highest measured plasma concentration during the sampling period. Comparing Cmax under midazolam-alone and co-administration conditions can help characterize whether exposure near the observed peak changes when givinostat is present. This endpoint is one part of a pharmacokinetic profile; it does not by itself describe every feature of exposure, such as the full concentration-time course.

Geometric means are commonly used for pharmacokinetic measures that are analyzed on a multiplicative scale. A confidence interval communicates uncertainty around an estimated mean; it is not a range expected to contain every individual subject’s measurement. The registry record does not report the numerical Cmax estimates or confidence intervals, so the magnitude, direction, and precision of any observed change cannot be assessed from the posted results. Numerical results for dabigatran pharmacokinetics are also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a pharmacokinetic study in which plasma concentrations of midazolam and 1-hydroxymidazolam were measured after single doses of intravenous or oral midazolam. The main reported endpoint definition is Cmax, summarized as a geometric mean with a 95% confidence interval. The study objectives also include potential effects of givinostat on oral dabigatran etexilate pharmacokinetics, although numerical dabigatran results are not reported in the registry record.

What does Cmax measure?

As a general statistical and pharmacokinetic explanation, Cmax is the highest observed concentration in the sampling period. It depends on the sampling schedule: the observed maximum is the highest measured value, and a peak between sampling times may not be captured. The registry gives sampling times extending through 24 hours after dosing for both intravenous and oral midazolam. The schedule is part of how the endpoint is defined, not a guarantee that every possible concentration peak was observed exactly.

Cmax is useful for studying a potential drug interaction because a change in the measured peak may indicate a change in one aspect of plasma exposure. It is not a complete description of the concentration-time profile. Other pharmacokinetic measures may address different aspects of exposure, but their numerical results are not reported in the registry record.

Why use geometric means?

As a general statistical explanation, pharmacokinetic measurements often have a right-skewed distribution and are commonly analyzed on a logarithmic scale. A geometric mean describes a central value on a multiplicative scale, rather than an arithmetic average of the original measurements. This can be appropriate when relative changes are of interest. The registry specifies geometric means for the primary endpoint, but does not report the individual values or numerical estimates needed to examine the distribution or reproduce the analysis.

What does the confidence interval communicate?

As a general explanation, a 95% confidence interval expresses uncertainty around an estimated quantity under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, while the interval’s location gives context for the estimate. It is not a statement that 95% of individual concentrations fall within that interval. For this study, the registry specifies 95% confidence intervals but does not report their numerical limits for the primary Cmax endpoint. Precision therefore cannot be evaluated from the registry record.

How should the study conditions be compared?

The endpoint description names midazolam-alone conditions and co-administration conditions on different study days. These are planned condition comparisons within a single-group study, rather than comparisons between randomized independent groups. As a general statistical point, within-subject pharmacokinetic comparisons can account for stable differences between people when the same participants contribute measurements under multiple conditions. Their interpretation still depends on conduct and analysis details, including the availability of paired measurements, treatment sequence, and any carryover between conditions. The registry record does not report enough detail to evaluate all of these features.

The registry identifies a pharmacokinetic analysis population: subjects enrolled in Part 1 with evaluable pharmacokinetic data for at least one investigational medicinal product and without deviations affecting pharmacokinetic interpretation. This definition indicates that inclusion depended on the availability and interpretability of pharmacokinetic data. The number included in that population and the handling of missing or unevaluable measurements are not reported in the registry record.

What can the planning calculations tell readers?

As a general explanation, a sample-size calculation based on an observed effect is a planning illustration. It asks how many participants per arm might be needed under stated assumptions to detect a chosen fraction of that effect at a stated significance level and power. It is not the trial’s observed power and does not establish that the study was designed with that sample size. The assumptions recorded for such illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions do not describe this study’s single-group design, and the registry record does not report a sample-size justification for the trial. Any planning illustration should therefore be read as hypothetical, not as an observed study result.

For time-to-event settings, general methods may express sample size in terms of total events, while other settings may express it as participants per arm. This trial’s primary endpoint is a pharmacokinetic concentration measure, not a time-to-event endpoint. No additional sample-size interpretation can be made without numerical endpoint estimates and the relevant planning outputs.

10. Multiplicity, Missing Data and Analysis Populations

The study has more than one objective and multiple pharmacokinetic measures and conditions. The registry record lists 16 outcome measures and 36 analyses. However, the statistical plan for handling multiple comparisons is not reported in the registry record. In particular, the record does not state whether the analyses were organized into a prespecified hierarchy, whether any adjustment for multiple testing was planned, or how primary and exploratory comparisons were distinguished beyond the objective and endpoint descriptions.

As a general statistical consideration, examining multiple endpoints, conditions, or comparisons can increase the chance of at least one apparently notable result when each is assessed separately. Adjustment procedures or a prespecified testing hierarchy can address that issue, but the appropriate approach depends on the study’s aims and analysis plan. Because the relevant plan is not reported in the registry record, it would be inappropriate to assume either that multiplicity was controlled or that it was ignored.

The pharmacokinetic analysis population is defined as subjects with evaluable data for at least one investigational medicinal product and no deviations affecting pharmacokinetic interpretation. The record does not report the number analyzed for each endpoint or comparison, how missing samples were handled, or whether any subjects were excluded from particular analyses. The detailed statistical analysis plan, including treatment of incomplete concentration profiles, is not reported in the registry record.

These omissions limit assessment of the analysis population and the robustness of the reported findings. Since numerical primary endpoint results are not reported in the registry record, the impact of missing data, analysis exclusions, or multiplicity on any estimated effect cannot be evaluated. These points are limitations of what can be interpreted from the registry record, not evidence that a particular analysis choice was made.

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 4% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts separately from other adverse events for the Midazolam, Dabigatran, and Givinostat groups. For each group, 26 were listed at risk for serious adverse events and 0 were reported as affected; the record also lists 0 deaths. For other adverse events, 26 were listed at risk and 26 were reported as affected in each group.

These are counts as recorded, not rates calculated from the counts. They should not be added across the three group labels: the study is described as single-group, and the labels do not establish three independent sets of participants. The group-specific figures therefore cannot be treated as separate randomized-arm comparisons or as evidence of a difference between drugs.

The record’s secondary outcomes include adverse-event counts and the incidence of participants with at least one adverse event by severity, with severity categories of mild, moderate, and severe. The detailed severity results are not reported in the registry record. The serious adverse event figures do not describe the types, timing, relatedness, or clinical course of events, and the other-event counts do not identify which events occurred under which dosing condition. No causal attribution can be inferred from these counts alone.

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

The study was designed to assess whether oral givinostat could influence the single-dose pharmacokinetics of intravenous or oral midazolam and oral dabigatran etexilate. Its midazolam endpoint was Cmax for midazolam and 1-hydroxymidazolam, with geometric means and 95% confidence intervals specified. The registry record also describes blood sampling through 24 hours after midazolam administration and reports adverse-event counts.

Those design details explain what the investigators intended to measure, but they do not reveal the observed pharmacokinetic findings. Numerical Cmax estimates, confidence intervals, and dabigatran pharmacokinetic results are not reported in the registry record. It is therefore not possible to say from this record whether concentrations changed, in which direction they changed, or how precise any estimated change was. The terms potential inhibition and potential induction name the questions being investigated; they are not findings.

As a general statistical distinction, the absence of a numerical result in a registry record is not evidence that an effect was absent. It means that the effect cannot be quantified or assessed from the information reported there. Similarly, an objective does not establish an outcome, and a confidence-interval method listed in an endpoint description does not supply the missing interval estimates.

The record’s safety counts indicate 0 serious adverse events and 0 deaths in each listed group, alongside 26 affected by other adverse events in each group. These descriptive data do not specify event identities or severity details. They should not be read as proof of safety or as proof that a particular drug caused an event. The study’s stated secondary objective was safety and tolerability, but the available counts alone do not provide a full safety assessment.

The findings that can be described are thus limited to the study design, objectives, endpoint definition, sampling schedule, and reported adverse-event counts. Any claim about the size or clinical meaning of a pharmacokinetic interaction would require numerical endpoint results and their uncertainty, which are not reported in the registry record.

13. Why This Trial Matters Statistically

Drug-drug interaction studies ask whether one drug changes the exposure to another. Statistically, this requires measurements under clearly defined dosing conditions and an analysis that quantifies the contrast between them. This study’s registry description identifies a repeated-condition pharmacokinetic question: midazolam alone and midazolam co-administered with givinostat, with conditions designated for potential inhibition and induction. It also identifies a question about oral dabigatran etexilate.

The endpoint illustrates why measurement and interpretation need to be kept distinct. Cmax is a defined summary of the concentration-time data, and geometric means with 95% confidence intervals are specified as the reporting approach. Those choices clarify the intended analysis, but without the numerical estimates they do not show the observed effect or its precision. A rigorous interpretation requires both the endpoint definition and the estimates produced from the data.

The design is also statistically important. This was an open-label, single-center, single-group study with allocation recorded as not applicable. It was not a randomized, masked parallel-group trial. Recognizing that distinction prevents inappropriate descriptions of its conditions as independent treatment arms and keeps interpretation aligned with the stated study model.

Finally, the registry illustrates the difference between a stated objective and a reported result. It lists potential inhibitory and inducing effects as questions, and it reports descriptive adverse-event counts. Numerical primary pharmacokinetic results are not reported in the registry record. That distinction matters because readers should not infer an interaction, its direction, or its magnitude solely from the study’s aims or schedule. The record permits a clear account of what was intended and how it was measured, while leaving the central numerical pharmacokinetic result unresolved.

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 main limitation for interpreting this trial from the registry record is that numerical primary pharmacokinetic results are not reported. Although the endpoint is specified as Cmax for midazolam and 1-hydroxymidazolam, the record does not include the geometric means, confidence intervals, or comparisons needed to characterize an observed effect. Numerical dabigatran pharmacokinetic results are also not reported in the registry record.

The available dosing description is incomplete. It names study days and several drug doses, but part of the oral midazolam schedule is truncated, and the complete givinostat dosing regimen is not established by the record. The listed givinostat concentration is not the same as a reported administered dose. The registry record also does not report a washout interval or enough detail to assess the full sequence and possible carryover between conditions.

The study was open-label, single-center, and single-group, with no randomized independent-arm comparison. These features do not invalidate a pharmacokinetic assessment, but they limit the kinds of comparative claims that can be made. The record does not report the number of participants contributing evaluable data to each endpoint, the handling of missing samples, or details of the analysis for incomplete concentration profiles.

Multiplicity methods and the detailed statistical plan are not reported in the registry record, despite the listing of 16 outcome measures and 36 analyses. The reported adverse-event counts also lack event identities and severity detail in the registry record. Consequently, neither the pharmacokinetic findings nor the safety profile can be fully assessed from the registry record alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity — NCT05492318.
• Registry record last updated 2025-01-06; status last verified 2024-12.
• Results first posted 2025-01-06.
• 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

NCT05492318 is a completed phase 1, open-label, single-center study in healthy subjects, with enrollment of 26. Its primary objectives concerned potential inhibitory and inducing effects of oral givinostat on single-dose pharmacokinetics of intravenous or oral midazolam and oral dabigatran etexilate. The specified primary endpoint was Cmax for midazolam and 1-hydroxymidazolam, summarized using geometric means and 95% confidence intervals.

The registry describes sampling through 24 hours after intravenous and oral midazolam. It reports 0 serious adverse events and 0 deaths for each listed group, with 26 affected by other adverse events in each group. Numerical primary pharmacokinetic estimates and detailed adverse-event results are not reported in the registry record. The study’s design and objectives can be described, but the size and precision of any pharmacokinetic effect cannot be assessed from the record.