Cardiac Safety Evaluation of P03277

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: P03277 0.1 mmol/kg; Drug: Moxifloxacin 400mg; Drug: NaCl 0.9%; Drug: P03277 0.3 mmol/kg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • Clinical Pharmacology unit, SGS-Life Science Service

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1; 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; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol; Drug: Moxifloxacin 400mg; One tablet per os; Drug: NaCl 0.9%; Single intravenous bolus injection at 2 mL/sec; Drug: P03277 0.3 mmol/kg; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol
Experimental: Sequence 2; 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; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol; Drug: Moxifloxacin 400mg; One tablet per os; Drug: NaCl 0.9%; Single intravenous bolus injection at 2 mL/sec; Drug: P03277 0.3 mmol/kg; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol
Experimental: Sequence 3; 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; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol; Drug: Moxifloxacin 400mg; One tablet per os; Drug: NaCl 0.9%; Single intravenous bolus injection at 2 mL/sec; Drug: P03277 0.3 mmol/kg; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol
Experimental: Sequence 4; 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; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol; Drug: Moxifloxacin 400mg; One tablet per os; Drug: NaCl 0.9%; Single intravenous bolus injection at 2 mL/sec; Drug: P03277 0.3 mmol/kg; Single intravenous bolus injection at 2 mL/sec; Other Names: Gadopiclenol

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Guerbet
• Investigators: Principal Investigator: Frederic Vanhoutte, MD, SGS Clinical Pharmacology Unit

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2017
• Primary Completion (Actual): June 7, 2018
• Study Completion (Actual): June 7, 2018

Study Registration Dates

• First Submitted: August 31, 2018
• First Submitted That Met QC Criteria: August 31, 2018
• First Posted (Actual): September 5, 2018

Study Record Updates

• Last Update Posted (Actual): July 18, 2022
• Last Update Submitted That Met QC Criteria: March 22, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: ECG; Cardiac safety; Gadolinium-based contrast agent; Gadopiclenol
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: GDX-44-006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No