Cardiac Safety Evaluation of P03277

Study Overview
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Brief Summary
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The study is a Phase I, Single center, Randomized, Cross-over Double-blind Placebo-controlled and Open-label Positive-controlled (moxifloxacin) in healthy volunteers. The primary objective is to assess the cardiac safety after administration of P03277 to 48 healthy volunteers at dose of 0.1 mmol/kg (anticipated clinical dose) and 0.3 mmol/kg (supra-clinical dose) by evaluating the QT and QTc intervals.

Detailed Description
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Each subjects will be administered with 4 products (P03277 at the 2 different doses, placebo and moxifloxacin) in a 4*4 cross over sequence balanced for first order carry over effect. Twelve subjects will be assigned to each sequence (6 males and 6 females). The volunteers will be enrolled sequentially by cohort of 8 subjects. ECG measurements will be compared with ECG parameters collected after administration of placebo (Nacl 0.9%). The test sensitivity will be assessed using a positive control (moxifloxacin 400 mg per os) known to induce delays in QT intervals.

Official Title
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Thorough QT/QTc Study to Assess the Electrocardiographic Safety of a New Gadolinium-based Contrast Agent P03277 in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: P03277 0.1 mmol/kg
* Drug: Moxifloxacin 400mg
* Drug: NaCl 0.9%
* Drug: P03277 0.3 mmol/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject assessed as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination) Subject with a Body Mass Index (BMI) > 19 kg/m² and < 28 kg/m² and a weight at least of 40 kg for female and 50 kg for male and at maximum of 100 kg Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Williams design for a 4*4 cross over
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1<br>The sequence of administration is: P/ScD/PC/CD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os). | Drug: P03277 0.1 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;Drug: Moxifloxacin 400mg<br>* One tablet per os<br>Drug: NaCl 0.9%<br>* Single intravenous bolus injection at 2 mL/sec<br>Drug: P03277 0.3 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;|
| Experimental: Sequence 2<br>The sequence of administration is: CD/PC/ScD/P Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os). | Drug: P03277 0.1 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;Drug: Moxifloxacin 400mg<br>* One tablet per os<br>Drug: NaCl 0.9%<br>* Single intravenous bolus injection at 2 mL/sec<br>Drug: P03277 0.3 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;|
| Experimental: Sequence 3<br>The sequence of administration is: ScD/CD/P/PC Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os). | Drug: P03277 0.1 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;Drug: Moxifloxacin 400mg<br>* One tablet per os<br>Drug: NaCl 0.9%<br>* Single intravenous bolus injection at 2 mL/sec<br>Drug: P03277 0.3 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;|
| Experimental: Sequence 4<br>The sequence of administration is: PC/P/CD/ScD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os). | Drug: P03277 0.1 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;Drug: Moxifloxacin 400mg<br>* One tablet per os<br>Drug: NaCl 0.9%<br>* Single intravenous bolus injection at 2 mL/sec<br>Drug: P03277 0.3 mmol/kg<br>* Single intravenous bolus injection at 2 mL/sec<br>* Other names: Gadopiclenol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The study had to show that both 0.1 and 0.3 mmol/kg doses of P03277 do not increase the QT interval corrected by Fridericia formula (QTcF). The study is successful if the difference between each of the two doses of P03277 and placebo for the largest mean change from baseline for the QTcF is lower than 10 milliseconds. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The assay sensitivity was assessed through this outcome. The difference between the positive control (moxifloxacin) and placebo for the largest mean change from baseline for the QTcF had to be greater than 5 milliseconds for at least one time point. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration. | from 1 hour before any administration until 4 hours post-administration at the following timepoints: -1 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours. | 
| Predicted Value of ∆∆QTc at Cmax | Concentration-response relationship was investigated between ∆QTc and P03277 concentrations using a mixed model approach. Plasma concentration of P03277 was measured at the same timepoints as ECG measurements. | from 1 hour before any administration until 24 hours post-administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac safety, ECG, Gadolinium-based contrast agent, Gadopiclenol