The purpose of this study is to assess the electrocardiogram (ECG) effects of fedovapagon dose administration relative to placebo in healthy adult male and female subjects.
Regulatory guidance (ICH E14) has emphasized the need to obtain clear robust data on the effect of new chemical entities on ECG parameters with focus on cardiac repolarization as measured by the QTc duration. Though many Phase 1, 2 and 3 trials may be conducted they usually have insufficient sample size, infrequent sampling of ECG data, or the use of inadequate controls to overcome the high rate of spontaneous change in QTc duration. This has resulted in regulatory guidance recommending a dedicated or thorough trial to define the ECG effects of new drugs. This study will be conducted in healthy volunteers to eliminate variables known to have an effect on ECG parameters (concomitant drugs, diseases, etc.). A supra-therapeutic dose of fedovapagon is required to mimic the exposure in healthy volunteers that may occur in the target population under the worst of circumstances (e.g., concomitant use of CYP3A4 inhibitor, concomitant liver disease, presence of heart disease, taking more than the clinical dose prescribed, etc.) and to allow for PK to QTc modeling to assess the effect of drug concentration on cardiac repolarization. A cross-over trial is the preferred design as subjects act as their own controls and since there is no accumulation of any clinical relevance and the plasma concentration of parent dissipates before 24 hours, a single dose trial will be employed. During the course of the study each subject will be administered fedovapagon at both a clinical and supra-therapeutic dose, placebo and moxifloxacin (as a positive control). The sample size is driven by the need to do a time-matched statistical analysis on the primary endpoint as per ICH E14 guidance.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
43
PAREXEL Early Phase Clinical Unit Berlin
Berlin, Germany
Time-matched change from baseline in QTc, placebo-adjusted and corrected for heart rate
Time frame: 0-48 hours
Heart rate
Time frame: 0-48 hours
PR interval
Time frame: 0-48 hours
QRS interval
Time frame: 0-48 hours
Uncorrected QT interval
Time frame: 0-48 hours
ECG morphology especially on repolarization
Time frame: 0-48 hours
Correlation between the QTc change from baseline and plasma concentrations of fedovapagon
Time frame: 0-48 hours
Number and type of adverse events
Time frame: 0-48 hours
The observed maximum plasma concentration (Cmax)
Time frame: 0-48 hours
Time to reach maximum plasma concentration (tmax)
Time frame: 0-48 hours
Apparent terminal half-life (t½)
Time frame: 0-48 hours
Area under the plasma concentration-time curve (AUC0-t), (AUC0-24h) and (AUC0-∞)
Time frame: 0-48 hours
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