Cardiac Safety Evaluation of P03277

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: P03277 0.1 mmol/kg
Drug: Moxifloxacin 400mg
Drug: NaCl 0.9%
Drug: P03277 0.3 mmol/kg

Registration Number: NCT03657264

Lead Sponsor: Guerbet

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 48

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 1	P03277 0.1 mmol/kg	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).
Sequence 1	Moxifloxacin 400mg	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).
Sequence 1	NaCl 0.9%	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).
Sequence 1	P03277 0.3 mmol/kg	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).
Sequence 2	P03277 0.1 mmol/kg	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).
Sequence 2	Moxifloxacin 400mg	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).
Sequence 2	NaCl 0.9%	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).
Sequence 2	P03277 0.3 mmol/kg	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).
Sequence 3	P03277 0.1 mmol/kg	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).
Sequence 3	Moxifloxacin 400mg	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).
Sequence 3	NaCl 0.9%	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).
Sequence 3	P03277 0.3 mmol/kg	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).
Sequence 4	P03277 0.1 mmol/kg	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).
Sequence 4	Moxifloxacin 400mg	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).
Sequence 4	NaCl 0.9%	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).
Sequence 4	P03277 0.3 mmol/kg	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).

Primary Outcome Measures

Name	Time	Method
Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)	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.	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.

Secondary Outcome Measures

Name	Time	Method
Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)	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.	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.
Predicted Value of ∆∆QTc at Cmax	from 1 hour before any administration until 24 hours post-administration.	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.