Cardiac Safety Evaluation of P03277: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cardiac Safety Evaluation of P03277 (NCT03657264), a randomized phase 1 study. The primary outcome is Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF).

2. Clinical Question

The endpoint concerns change in the QT interval corrected using Fridericia’s formula. The record describes repeated ECG assessments from 1 hour before administration through 24 hours after administration. It also lists secondary outcomes concerning moxifloxacin’s effect on QTcF and the predicted value of the concentration-related QTc change at Cmax.

3. Trial Design

This was a randomized, triple-masked, crossover Phase I study sponsored by Guerbet. The registry describes it as single-center, double-blind and placebo-controlled, with an open-label positive-control treatment. It enrolled 48 healthy volunteers and is marked completed. The recorded study start was 2017-08-21, and primary completion was 2018-06-07.

Rather than assigning participants to separate parallel groups that each received only one product, the crossover design used four treatment sequences. The sequences varied the order of placebo, P03277 at 0.1 mmol/kg, P03277 at 0.3 mmol/kg, and oral moxifloxacin 400 mg. Thus, the intended comparisons were made across treatments administered within the study’s sequence structure. The registry does not report the sequence-specific participant counts or further operational details such as washout periods.

The primary objective was to assess cardiac safety by evaluating QT and QTc intervals after both P03277 doses. ECG monitoring used a 12-lead Holter. The primary endpoint was change from baseline in QTcF, with the baseline defined as the mean of the 3 triplicate ECG measurements within 1 hour before each product administration. Measurements were scheduled from 1 hour before administration through 24 hours after administration at the listed timepoints.

Moxifloxacin was included as a positive control, while NaCl 0.9% served as placebo. The registry lists 3 outcome measures and 27 analyses. It does not report the study’s detailed statistical analysis plan, the rationale for its enrollment target, or whether interim analyses were planned or conducted.

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: The primary analysis was performed using the per protocol set which included subjects who had no major protocol deviations throughout their whole study period.

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 Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF), measured over from 1 hour before any administration until 24 hours post-administration at the following timepoints: -1 hour, 5 min, 10 min, 20 min, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours..

The primary endpoint measures the change from baseline in the mean QT interval corrected by Fridericia’s formula, usually denoted QTcF. The QT interval is an ECG measure of the time from the start of ventricular electrical activation through recovery. Correction for heart rate aims to make QT measurements more comparable when heart rate varies. This is a general description of the measure, not a statement about the study’s results.

For this study, baseline was defined as the mean of 3 triplicate ECG measurements collected within 1 hour before each product administration. Participants were monitored with a 12-lead Holter ECG. The stated timeframe began 1 hour before administration and continued through 24 hours post-administration, with measurements at the registry-listed timepoints.

The primary objective was to compare the largest mean change from baseline for each P03277 dose with placebo. The registry’s success criterion was that the difference for each dose be lower than 10 milliseconds. This criterion describes the planned interpretation of the endpoint; it does not establish that either comparison met the criterion. The numerical endpoint results, their uncertainty, and whether the success criterion was met are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a least-squares mean as the primary endpoint parameter and a standard error as its dispersion measure. It does not provide the estimates themselves or a detailed statistical analysis plan. The explanations below describe these statistical concepts generally; they should not be read as a reconstruction of the model used in this trial.

What is a least-squares mean?

In general, a least-squares mean is a model-based estimate of an outcome mean, adjusted for the terms included in the statistical model. It can be useful when a study design has structured features, such as treatment sequence or repeated observations, and the analysis aims to compare treatments while accounting for such features. The precise interpretation depends on which terms the model includes, how observations are handled, and what contrast is estimated. The registry record does not report those model specifications, so the adjustment represented by its stated least-squares mean cannot be described in more detail.

For a crossover study, a model might account for treatment and period, among other design features. That is a general possibility, not a claim about this analysis. Whether sequence, participant, baseline, or carryover terms were included is not reported in the registry record. Nor is the method for choosing the largest mean change across the repeated ECG timepoints reported.

What does the standard error describe?

Generally, a standard error describes the estimated sampling variability of an estimate under the analysis model. It is not the same as the spread of individual participants’ measurements. A smaller standard error indicates greater precision in the estimated mean under that model, while a larger standard error indicates less precision. Here, the registry names standard error as the dispersion measure but does not report numerical standard errors for the primary comparisons.

A confidence interval is a range calculated using an estimate and its uncertainty to express the precision of that estimate under specified statistical assumptions. In general, an interval that is narrow indicates more precision than a wide interval. No confidence interval for the P03277-versus-placebo primary contrasts is reported in the registry record. Without an estimate and its uncertainty, the distance from the stated 10-millisecond criterion cannot be judged.

How does the crossover structure matter?

In general, a crossover design can compare treatments within participants, which may account for stable differences between participants. It also creates dependence among observations from the same participant: those measurements should not be treated as if they came from unrelated people. Treatment order and time period may also matter. Appropriate analysis needs to reflect the design and the assumptions relevant to treatment effects over periods.

The registry records four sequences, each containing placebo, both P03277 doses, and moxifloxacin in a different order. It does not report how the analysis modeled sequence or period, whether the data supported the crossover assumptions, or how potential carryover was assessed. These details are important for judging whether estimated treatment contrasts represent the comparisons intended by the design.

Why include a positive control?

Generally, a positive control is an active comparator included to help assess whether the study can detect an expected type of response under its conditions. Moxifloxacin served that role in this study, and its QTcF effect was listed as a secondary outcome. The control’s inclusion does not itself show that it produced a particular response. Its estimate and uncertainty are not reported in the registry record.

What does the planning illustration mean?

The registry describes a sample-size planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is a total number of events; for other outcomes, it is participants per arm. These are planning assumptions, not evidence about the trial’s observed power. The numerical planning outputs and the trial’s own sample-size justification are not reported in the registry record.

More generally, planning calculations estimate the enrollment needed under specified assumptions; they do not reveal how likely the completed trial was to detect an effect after the results are known. The trial’s enrollment of 48 is recorded, but the rationale for that enrollment and any assumptions about the expected treatment contrast or variability are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 27 analyses. The primary outcome description includes multiple measurement timepoints, and the record notes that it has several categories or timepoints rather than one reduced comparison. Repeated outcomes and multiple analyses raise a general multiplicity issue: the more estimates or tests considered, the greater the chance that some results may appear notable by chance if the analysis does not account for the number of comparisons.

The record does not report a multiplicity adjustment, a hierarchy of outcomes, a prespecified testing sequence, or which analyses were confirmatory versus exploratory. It also does not report how the largest mean change across timepoints was selected for the primary comparison. Therefore, the degree to which multiplicity was addressed cannot be assessed. This is a limitation of the available reporting, not evidence that no adjustment was used.

The primary analysis population is described as the per-protocol set, including subjects without major protocol deviations throughout their whole study period. The number included in that set, exclusions, and reasons for exclusion are not reported in the registry record. The record also does not report whether an intention-to-treat or other analysis population was used for any outcome.

Missing ECG observations, withdrawal handling, imputation methods, and sensitivity analyses are not reported in the registry record. In general, missing-data methods matter because analyses can be affected when observations are unavailable, especially if missingness is related to treatment or outcome. Without details of missingness and its handling, the robustness of the endpoint analysis cannot be evaluated.

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 registry lists zero serious adverse events and zero deaths for each of the four treatment groups: P03277 0.1 mmol/kg, P03277 0.3 mmol/kg, positive control moxifloxacin, and placebo. Each group has 48 participants recorded as at risk for serious adverse events and deaths. These are the registry’s group-level figures; they do not by themselves establish that no events occurred outside the recorded reporting period or under other definitions.

The record also lists participants affected by other, non-serious adverse events: 25 for P03277 0.1 mmol/kg, 22 for P03277 0.3 mmol/kg, 16 for moxifloxacin, and 22 for placebo. These figures are not a substitute for the primary QTcF results and do not indicate the severity, timing, or causal relationship of individual events. The registry does not list serious adverse-event terms.

Because this was a crossover study, the same participants could receive multiple products in different periods. Group-level adverse-event figures should therefore be read as treatment-period reporting, not as separate parallel groups. The record does not provide event-level descriptions or further detail about attribution.

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

The registry record establishes that the study was designed to examine QTcF changes after two P03277 doses in healthy volunteers, with placebo comparison and moxifloxacin as a positive control. It also states a success criterion involving the largest mean change from baseline and a 10-millisecond boundary. Those design details define the question the study was intended to address.

They do not reveal the observed QTcF response. Numerical primary estimates, standard errors, confidence intervals, and p-values are not reported in the registry record. Consequently, it is not possible from these registry entries to determine whether either P03277 comparison met the stated criterion, how close an estimate was to that boundary, or how precisely the effect was estimated. The completed status is not a substitute for outcome data.

The same caution applies to the secondary outcomes. The registry lists moxifloxacin’s change-from-baseline QTcF effect and the predicted value of the concentration-related QTc change at Cmax, but their results are not reported in the registry record. The design identifies how these questions fit into the study; it does not establish their answers.

The safety figures indicate that the registry records zero serious adverse events and zero deaths in each treatment group, while also listing other adverse events. These descriptive counts should not be interpreted as proof of an absence of risk. They do not provide detailed event-level information or establish whether an event was caused by a study product.

In general, clinical interpretation depends on the size and precision of treatment contrasts, the analysis population, the handling of repeated measurements and missing data, and the study’s limitations. Several of these details are not reported in the registry record. The available information therefore supports a description of the trial’s design, endpoint, and recorded adverse-event figures, but not a conclusion about the primary QTcF findings.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a crossover structure with repeated ECG measurements and a maximum-change criterion. The design compares multiple treatments across sequences, while the endpoint follows QTcF over a series of post-administration timepoints. These features make the definition and analysis of the treatment contrast central to interpretation.

General statistical reasoning highlights two linked questions. First, repeated observations from the same participant are related, so analysis should reflect that dependence. Second, looking across several timepoints and focusing on the largest change raises questions about how the selected contrast was defined and how multiple comparisons were handled. The registry identifies the measurement schedule and the success criterion, but does not report the model details or multiplicity strategy.

The stated criterion is also clinically interpretable as a boundary on the difference from placebo in the largest mean change. For a boundary-based question, estimates and their uncertainty are essential: the point estimate alone would not describe precision, and a test result alone would not convey the size of the effect. The numerical primary results needed for that assessment are not reported in the registry record.

The positive control adds a further design feature, since moxifloxacin was included and its QTcF effect was listed as a secondary outcome. Its observed response would be relevant to understanding the study’s performance, but that result is not reported in the registry record.

These features make the record useful for identifying the statistical questions a thorough QT/QTc study raises, while its missing numerical outcomes prevent assessment of the answers. The distinction between a clearly stated design objective and an available result is important when reading registry information.

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 limitation for interpreting this trial is that numerical results for the primary QTcF endpoint are not reported in the registry record. The largest mean changes, P03277-versus-placebo contrasts, uncertainty estimates, and the determination of whether the success criterion was met are unavailable. The registry’s completed status does not resolve this gap.

The record describes an analysis in the per-protocol set, defined by the absence of major protocol deviations throughout the study period. It does not report the number analyzed, the exclusions, or whether other analysis populations were used. This makes it difficult to assess how the analysis population relates to enrollment.

Several methodological details are not reported in the registry record: the statistical model, treatment of period and sequence, handling of possible carryover, approach to the repeated timepoints, and method for selecting the largest mean change. The record also does not report a multiplicity strategy, missing-data methods, or sensitivity analyses. These omissions prevent evaluation of important assumptions and analytic choices; they do not prove that the study failed to address them.

The registry identifies four treatment sequences but does not give their participant counts or operational details such as washout periods. It also provides no numerical result for the moxifloxacin positive control or the listed concentration-related secondary outcome. Finally, results in healthy volunteers and the registry’s safety summaries should be understood within the population and reporting scope recorded, without extending them beyond the study information available.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Cardiac Safety Evaluation of P03277 — NCT03657264.
• Registry record last updated 2022-07-18; status last verified 2022-03.
• Results first posted 2019-08-22.
• 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

NCT03657264 is a completed, randomized, triple-masked, crossover Phase I study sponsored by Guerbet. It enrolled 48 healthy volunteers and evaluated P03277 at 0.1 mmol/kg and 0.3 mmol/kg, with NaCl 0.9% as placebo and oral moxifloxacin 400 mg as positive control. Four treatment sequences varied the administration order.

The primary endpoint was change from baseline in QTcF, measured using 12-lead Holter ECG monitoring from 1 hour before administration through 24 hours after administration. The registry’s stated success criterion was that the difference from placebo for each P03277 dose in the largest mean change be lower than 10 milliseconds.

Numerical primary and secondary outcome results, detailed model specifications, multiplicity handling, and missing-data methods are not reported in the registry record. The adverse-event record lists zero serious adverse events and zero deaths in each group, alongside other adverse-event figures.