Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval (NCT04821063), a randomized phase 1 study. The primary outcome is Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval (QTcF).

2. Clinical Question

3. Trial Design

This was a randomized, four-period, four-treatment crossover study described as Phase 1. The official title calls it partially double-blind, while the registry’s masking classification is quadruple. Those descriptions are not identical, and the registry record does not explain the difference. It lists Italfarmaco as sponsor and reports enrollment of 31 participants. The study is marked completed; its recorded start date is 2021-04-13 and its primary completion date is 2021-06-18.

The four treatments named in the record were ITF2357 100 mg, ITF2357 300 mg, placebo, and moxifloxacin. Participants were assigned treatment sequences, with doses described as single administrations on Day 1 of the respective period. The therapeutic dose description specifies 10 mL of ITF2357 10 mg/mL oral suspension and 20 mL of matched placebo; the supratherapeutic dose description specifies 30 mL of ITF2357 10 mg/mL oral suspension. Placebo was described as a 30 mL oral suspension, and moxifloxacin as a 400 mg tablet. The registry does not report the sequences, period duration, washout intervals, or details of how masking was maintained.

A crossover design compares treatments within participants across periods, which can reduce the influence of stable differences between participants. Its interpretation can depend on period effects, order effects, and whether effects persist between periods. These are general considerations; the registry record does not report the methods used to assess them. The endpoint population was defined as participants in the safety population with baseline and at least one valid post-dose ΔQTcF value. This definition is specific to the primary measure and does not establish how many participants contributed at each time point.

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: Participants were administered the following treatments: Treatment T (Therapeutic dose of ITF2357 100 mg), Treatment ST (Supratherapeutic dose of ITF2357 300 mg), Treatment P (Placebo), and Treatment M (Moxifloxacin) in 4-periods and 12-sequences in this study.

Only the first 6 of 12 groups are shown.

Period 1 (1 Day)

Washout Period (7 Days )

Period 2 (1 Day)

Washout Period (7 Days)

Analysis population for the primary outcome, as defined in the registry: The QT/QTc Population was defined as all participants in the safety population with measurements at baseline as well as on-treatment with at least one post-dose time point with a valid ΔQTcF value. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

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: Safety population included all participants who had received at least 1 dose of study drug (therapeutic and supratherapeutic doses of ITF2357, moxifloxacin, or placebo). All participants had multiple movement within the arms of the study at different levels and unique participants baseline was not analyzed, only overall participant data was planned, analyzed and reported to avoid double-counting.

6. Primary Endpoint

The registry lists the primary outcome as Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval (QTcF), measured over At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose.

The primary endpoint was placebo-corrected change from baseline in Fridericia-corrected QT interval (QTcF), measured in milliseconds. The QT interval runs from the ECG Q wave to the end of the T wave and corresponds to electrical systole. Because QT varies with heart rate, the study used Fridericia’s correction to express the interval as QTcF. The primary measure, ΔΔQTcF, was calculated from a model-predicted effect and contrasted with placebo.

In general, placebo correction helps distinguish change associated with the active treatment from change also observed under placebo. A baseline comparison accounts for the participant’s starting measurement, while heart-rate correction is intended to make QT measurements more comparable across different heart rates. These adjustments address different sources of variation; they do not eliminate all uncertainty or guarantee that the estimate is unbiased.

ECGs were extracted from continuous 12-lead recordings at prespecified post-dose times: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours. Participants rested supine before and after each ECG extraction, as described in the registry. Repeated measurements can characterize how an effect changes over time, but they also create multiple results requiring careful interpretation. The numerical endpoint estimates, standard errors, and inferential results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does placebo correction mean?

Placebo correction compares the change observed under an active treatment with the change observed under placebo. In general, this can help separate treatment-associated change from change related to time, measurement conditions, or other influences shared with the placebo period. The primary outcome was defined as placebo-corrected change from baseline in QTcF, calculated from model-predicted effect. The registry record does not report the model formula or its estimated results.

Why correct QT for heart rate?

The QT interval can vary with heart rate. Fridericia correction transforms the QT interval to a heart-rate-corrected measure, QTcF, for analysis. This is a general rationale for correction, not a guarantee that all heart-rate-related differences are removed. The registry describes QTcF as the primary measure and also lists heart rate among the secondary outcomes. It does not report the correction diagnostics or numerical heart-rate findings.

What does a least-squares mean represent?

A least-squares mean is generally an estimate from a statistical model, adjusted for the terms included in that model. In a crossover study, a model can account for the fact that participants receive multiple treatments across periods. The exact adjustment depends on the specified model. The registry record names least-squares mean as the parameter but does not report the model terms, estimates, or standard errors. It is therefore not possible to determine from the record how particular factors were handled.

How should standard error be read?

A standard error describes uncertainty in an estimated quantity under the statistical model. It is distinct from a standard deviation, which describes variation among observations. In general, a confidence interval combines an estimate with its uncertainty to show a range of values compatible with the data and specified method. No primary endpoint confidence intervals or standard errors are reported in the registry record, so the precision of the treatment estimates cannot be evaluated.

Why does the crossover structure matter?

In a crossover study, each participant receives treatments in different periods, allowing comparisons that can account for stable participant characteristics. This design can be efficient for outcomes that can be measured repeatedly and are expected to return to a suitable baseline between periods. General concerns include period effects, treatment order, carryover, and within-participant correlation. These concerns do not establish that a problem occurred in this study. The registry record does not report washout details, tests for carryover, or the model’s treatment of period and sequence.

Why are repeated time points important?

QTcF was assessed at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose. Repeated assessments can describe the timing and shape of a response. They also produce multiple estimates, and examining many estimates raises a multiplicity issue: the chance of a false-positive finding can increase when many hypotheses are tested without an appropriate strategy. This is a general statistical concern. The registry record does not report a multiplicity procedure or an analysis hierarchy. It indicates that the primary outcome had several time points and was not reduced to one comparison.

What can be inferred from the analysis population?

The QT/QTc population was defined as members of the safety population with baseline measurements and at least one valid post-dose ΔQTcF value. This is an outcome-specific evaluability rule. It does not mean every member contributed a valid value at every scheduled time. In general, missing measurements can affect estimates if the chance of being observed is related to treatment or outcome. The registry record does not report time-point-specific counts, reasons for missing ECG measurements, or methods for handling missing data.

What is the role of sample-size planning?

In general, sample-size planning uses assumptions about the effect to detect, variability, significance level, allocation, and desired power. The registry’s planning illustration is described as using a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such values are planning illustrations, not observed power and not proof that a study was adequately powered for every endpoint. The registry record does not report the trial’s own sample-size justification. No planning participant counts are reported in the record summary.

The important distinction is between a planned design calculation and evidence from the observed results. A planning calculation describes what a hypothetical design might require under its assumptions. It does not reveal the trial’s actual treatment estimates, uncertainty, or missing-data pattern. Since the registry record does not report numerical primary-outcome analyses, the endpoint cannot be interpreted by substituting a planning illustration for observed results.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome involves placebo-corrected change from baseline in QTcF at multiple post-dose time points. The registry record explicitly indicates that the primary outcome has several categories or time points and was not reduced to one comparison. It does not report which time points, if any, were designated as primary for formal inference, nor does it report a multiplicity adjustment or testing hierarchy. In general, evaluating many treatment contrasts or time points without controlling multiplicity can increase the chance of false-positive findings. The record does not establish whether or how this concern was addressed in the analysis.

The registry describes a QT/QTc analysis population requiring baseline and at least one valid post-dose value. This criterion does not reveal the number of evaluable participants at every time point. The enrollment count was 31, while the record does not report the endpoint-specific numbers contributing to each scheduled assessment. Reasons for missing measurements, the amount of missingness, and any imputation or other missing-data methods are not reported in the registry record.

The record also does not report a full statistical analysis plan, model specification, prespecified handling of outliers, or sensitivity analyses. These details matter in general because analysis choices can affect estimates and uncertainty, especially with repeated observations and incomplete follow-up. Their absence from the registry record should not be interpreted as evidence that no such methods were used; their status is not reported in the registry record.

There were no analyses listed in the record summary. Thus, there are no reported primary endpoint estimates or inferential results to evaluate for multiplicity, missing-data sensitivity, or robustness. The available descriptions establish the intended measure and population definition, but do not permit a detailed audit of the statistical analysis.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety summary lists serious adverse events, other adverse events, and deaths by treatment group. It reports zero serious adverse events among 29 participants at risk for the therapeutic ITF2357 100 mg dose, zero among 31 at risk for the 300 mg dose, zero among 31 at risk for placebo, and zero among 31 at risk for moxifloxacin. Deaths are reported as zero in every listed group.

For other adverse events, the record reports 5 affected participants in the 100 mg group, 15 in the 300 mg group, 6 in the placebo group, and 4 in the moxifloxacin group. The corresponding numbers at risk are 29, 31, 31, and 31. These are descriptive group counts; the registry record does not provide event-level detail in the safety summary. It lists no top serious-event terms.

These counts should not be treated as a statistical comparison of treatments. The study used a crossover design, and the record does not explain how safety exposure was attributed across periods or provide an inferential safety analysis. The group counts alone do not establish causation, relative risk, or the severity and clinical course of individual events. Zero reported serious events in these groups means none were recorded in this summary; it does not establish that a treatment has no serious risks.

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

The registry record establishes that the study was designed to examine the effect of therapeutic and supratherapeutic ITF2357 doses on placebo-corrected QTcF. It also identifies placebo and moxifloxacin as comparison treatments, describes a randomized crossover structure, and gives the scheduled ECG time points. These details define the clinical and statistical question, but they are not themselves evidence of the direction or magnitude of an effect.

Numerical primary endpoint results are not reported in the registry record. Therefore, the record does not show whether QTcF changed relative to placebo, how estimates varied over time, or how precisely any treatment contrast was estimated. It cannot support a conclusion about the size, clinical relevance, or statistical significance of the primary endpoint findings. The absence of reported results should not be read as evidence of no effect.

The description of a least-squares mean and standard error indicates the intended form of summary, but without the corresponding values it is not possible to assess uncertainty. Likewise, the schedule of repeated measurements signals that effects could be evaluated over time, but no time-specific treatment estimates are available. No single result can be substituted for the unreported time-course analyses.

The safety counts provide a separate descriptive view: no serious adverse events or deaths are listed for the four treatment groups, while other adverse events are reported in each group. These counts do not replace the primary ECG endpoint and do not provide a formal treatment comparison. The registry record does not provide detailed event terms or analysis sufficient to establish causation.

In general, statistical interpretation requires both an estimate and an assessment of uncertainty, together with knowledge of the analysis population and methods. Here, design and endpoint definitions are available, but the primary numerical results and key analytic details are not reported in the registry record. The appropriate reading is limited to what was planned and how the outcome was defined, not to an effectiveness or safety conclusion.

13. Why This Trial Matters Statistically

This trial raises statistical questions that are especially visible in a crossover ECG study. The same participants were assigned to receive multiple treatments across periods, and the primary outcome was measured repeatedly after dosing. That structure can support within-participant comparisons, but interpretation depends on accounting appropriately for treatment, time, period, and the correlation among repeated measurements. The registry record describes the design but does not report the model details needed to evaluate those choices.

The primary endpoint is a model-predicted, placebo-corrected change from baseline rather than a simple raw QT measurement. This distinction matters because model-based contrasts depend on both the outcome definition and the fitted analysis. Reporting the estimate alongside its uncertainty is central to understanding the strength and precision of the evidence. The registry record does not report these primary estimates.

Multiple post-dose times create a further interpretive challenge. A time course can be more informative than a single observation, but testing or emphasizing several time points requires a clear approach to multiplicity and prespecification. The registry indicates that the outcome spans several time points and was not reduced to one comparison, while the multiplicity strategy is not reported in the registry record.

The record also illustrates why an enrollment number cannot stand in for endpoint-specific information. The stated QT/QTc population requires valid measurements, but the number of participants contributing at each post-dose assessment is not reported. With repeated ECG data, availability and analysis methods can influence how the time profile is interpreted.

These features make the study’s statistical question clear even though its numerical findings are unavailable in the registry record. The design, endpoint, time schedule, and safety counts can be described, but they do not support a quantitative conclusion about QTcF effects without the actual treatment estimates and their uncertainty.

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 interpretation is that numerical primary endpoint results are not reported in the registry record. The record identifies the outcome as placebo-corrected change from baseline in QTcF and names least-squares mean and standard error, but it does not report the values, confidence intervals, or inferential results. As a result, the treatment contrasts and their precision cannot be assessed.

The endpoint was evaluated at numerous scheduled times, and the registry record does not state how those time points were prioritized or how multiplicity was handled. It also does not report a statistical analysis plan, detailed model specification, period and sequence effects, or sensitivity analyses. These details are relevant to judging a crossover analysis but cannot be reconstructed from the design description.

The registry’s outcome-population definition requires a baseline and at least one valid post-dose value, but time-point-specific participant counts and reasons for missing ECG data are not reported. The enrollment figure does not resolve how many participants contributed to each estimate. The record also does not provide washout details or report how potential carryover was assessed.

The official title describes the study as partially double-blind, whereas the masking classification says quadruple. The registry record does not clarify this difference. It also lists conditions that do not align straightforwardly with the healthy-subject population described in the official title; the record does not explain that listing. These are reporting ambiguities, not evidence of a particular protocol deviation.

The safety summary is limited to group counts. It does not provide detailed event descriptions or an inferential comparison, so those counts should be interpreted descriptively. Collectively, the available information supports a description of the study question and design, but not a complete assessment of its primary numerical findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval — NCT04821063.
• Registry record last updated 2024-01-11; status last verified 2023-04.
• Results first posted 2024-01-11.
• 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

NCT04821063 is a completed randomized Phase 1 crossover study sponsored by Italfarmaco. The official title describes a partially double-blind, four-period, four-treatment study in healthy male and female subjects; the registry masking classification is quadruple. Enrollment was 31, with a recorded start date of 2021-04-13 and primary completion date of 2021-06-18.

The study compared ITF2357 100 mg and 300 mg with placebo and moxifloxacin. Its primary endpoint was placebo-corrected change from baseline in QTcF, assessed at multiple post-dose times. Numerical primary endpoint analyses are not reported in the registry record. The safety summary lists zero serious adverse events and zero deaths across the four groups, along with other adverse events affecting participants in each group.