Healthy Volunteers
Conditions
Keywords
Gadolinium-based contrast agent, Cardiac safety, ECG, Gadopiclenol
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.
Interventions
DRUGP03277 0.1 mmol/kg
Single intravenous bolus injection at 2 mL/sec
One tablet per os
DRUGNaCl 0.9%
Single intravenous bolus injection at 2 mL/sec
DRUGP03277 0.3 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Sponsors
Guerbet
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Williams design for a 4\*4 cross over
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
Yes
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
\-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 12 |
| 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). | 12 |
| 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). | 12 |
| 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). | 12 |
| Total | 48 |
Baseline characteristics
| Characteristic | Total | Sequence 2 | Sequence 3 | Sequence 4 | Sequence 1 |
|---|---|---|---|---|---|
| Age, Continuous | 40.5 years STANDARD_DEVIATION 11.6 | 41.9 years STANDARD_DEVIATION 11.1 | 44.8 years STANDARD_DEVIATION 11.1 | 39.8 years STANDARD_DEVIATION 10.2 | 35.8 years STANDARD_DEVIATION 13.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 12 Participants | 12 Participants | 12 Participants | 11 Participants |
| Sex: Female, Male Female | 24 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 24 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
| Weight | 75.3 kg STANDARD_DEVIATION 9.9 | 77.6 kg STANDARD_DEVIATION 11.1 | 75.9 kg STANDARD_DEVIATION 8.3 | 71.3 kg STANDARD_DEVIATION 9.8 | 76.3 kg STANDARD_DEVIATION 10.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 48 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 25 / 48 | 22 / 48 | 16 / 48 | 22 / 48 |
| serious Total, serious adverse events | 0 / 48 | 0 / 48 | 0 / 48 | 0 / 48 |
Outcome results
Primary
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.
Time frame: 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.
Population: The primary analysis was performed using the per protocol set which included subjects who had no major protocol deviations throughout their whole study period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 3 hours | 2.34 milliseconds | Standard Error 0.98 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1 hour | -2.72 milliseconds | Standard Error 0.92 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 8 hours | -2.55 milliseconds | Standard Error 1.17 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 2 hours | -2.08 milliseconds | Standard Error 0.99 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1.5 hours | -3.08 milliseconds | Standard Error 0.89 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 5 min | 0.97 milliseconds | Standard Error 0.88 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 20 min | -1.25 milliseconds | Standard Error 0.88 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 10 min | -0.11 milliseconds | Standard Error 0.86 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 4 hours | 0.61 milliseconds | Standard Error 0.97 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 30 min | -1.06 milliseconds | Standard Error 0.79 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 24 hours | -3.18 milliseconds | Standard Error 0.92 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1.5 hours | -4.64 milliseconds | Standard Error 0.89 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 5 min | 5.05 milliseconds | Standard Error 0.89 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 10 min | 1.34 milliseconds | Standard Error 0.86 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 20 min | -1.20 milliseconds | Standard Error 0.88 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 30 min | -1.26 milliseconds | Standard Error 0.79 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1 hour | -2.44 milliseconds | Standard Error 0.92 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 2 hours | -3.22 milliseconds | Standard Error 0.99 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 3 hours | -1.38 milliseconds | Standard Error 0.98 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 4 hours | -0.51 milliseconds | Standard Error 0.97 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 8 hours | -5.59 milliseconds | Standard Error 1.17 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 24 hours | -3.28 milliseconds | Standard Error 0.92 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 8 hours | -3.66 milliseconds | Standard Error 1.17 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 3 hours | -0.05 milliseconds | Standard Error 0.98 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 20 min | -1.41 milliseconds | Standard Error 0.88 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 5 min | 0.24 milliseconds | Standard Error 0.89 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 4 hours | 0.33 milliseconds | Standard Error 0.97 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 10 min | -0.59 milliseconds | Standard Error 0.86 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1.5 hours | -3.53 milliseconds | Standard Error 0.89 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1 hour | -2.90 milliseconds | Standard Error 0.92 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 24 hours | -3.49 milliseconds | Standard Error 0.93 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 2 hours | -2.05 milliseconds | Standard Error 0.99 |
| Placebo | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 30 min | -1.69 milliseconds | Standard Error 0.79 |
Comparison: For the timepoint 5 min90% CI: [-1.23, 2.69]ANCOVA
Comparison: For the timepoint 10 min90% CI: [-1.32, 2.29]ANCOVA
Comparison: For the timepoint 10 min90% CI: [0.12, 3.73]ANCOVA
Comparison: For the timepoint 20 min90% CI: [-1.76, 2.08]ANCOVA
Comparison: For the timepoint 30 min90% CI: [-1.09, 2.35]ANCOVA
Comparison: For the timepoint 1 hour90% CI: [-1.88, 2.25]ANCOVA
Comparison: For the timepoint 1.5 hours90% CI: [-1.47, 2.37]ANCOVA
Comparison: For the timepoint 2 hours90% CI: [-1.99, 1.92]ANCOVA
Comparison: For the timepoint 3 hours90% CI: [0.35, 4.43]ANCOVA
Comparison: For the timepoint 4 hours90% CI: [-1.57, 2.12]ANCOVA
Comparison: For the timepoint 8 hours90% CI: [-1.15, 3.37]ANCOVA
Comparison: For the timepoint 24 hours90% CI: [-1.52, 2.14]ANCOVA
Comparison: For the timepoint 5 min90% CI: [2.84, 6.78]ANCOVA
Comparison: For the timepoint 20 min90% CI: [-1.71, 2.12]ANCOVA
Comparison: For the timepoint 30 min90% CI: [-1.29, 2.15]ANCOVA
Comparison: For the timepoint 1 hour90% CI: [-1.6, 2.53]ANCOVA
Comparison: For the timepoint 1.5 hours90% CI: [-3.03, 0.81]ANCOVA
Comparison: For the timepoint 2 hours90% CI: [-3.13, 0.78]ANCOVA
Comparison: For the timepoint 3 hours90% CI: [-3.36, 0.71]ANCOVA
Comparison: For the timepoint 4 hours90% CI: [-2.69, 1]ANCOVA
Comparison: For the timepoint 8 hours90% CI: [-4.19, 0.32]ANCOVA
Comparison: For the timepoint 24 hours90% CI: [-1.62, 2.04]ANCOVA
Secondary
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.
Time frame: 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.
Population: Analysis of secondary criteria was performed using the full analysis set which included all randomized subjects.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1.5 hours | 6.13 milliseconds | Standard Error 0.88 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 3 hours | 10.50 milliseconds | Standard Error 0.97 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 2 hours | 8.60 milliseconds | Standard Error 0.97 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 4 hours | 11.28 milliseconds | Standard Error 0.95 |
| P03277 0.1 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1 hour | 1.73 milliseconds | Standard Error 0.91 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 4 hours | 0.63 milliseconds | Standard Error 0.95 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1 hour | -2.89 milliseconds | Standard Error 0.91 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 1.5 hours | -3.27 milliseconds | Standard Error 0.88 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 2 hours | -1.95 milliseconds | Standard Error 0.97 |
| P03277 0.3 mmol/kg | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) | 3 hours | 0.17 milliseconds | Standard Error 0.97 |
Comparison: For the timepoint 1 hour90% CI: [2.58, 6.66]ANCOVA
Comparison: For the timepoint 1.5 hours90% CI: [7.14, 11.66]ANCOVA
Comparison: For the timepoint 2 hours90% CI: [7.92, 13.17]ANCOVA
Comparison: For the timepoint 3 hours90% CI: [7.7, 12.95]ANCOVA
Comparison: For the timepoint 4 hours90% CI: [8.05, 13.25]ANCOVA
Secondary
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.
Time frame: from 1 hour before any administration until 24 hours post-administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| P03277 0.1 mmol/kg | Predicted Value of ∆∆QTc at Cmax | 0.41 milliseconds |
| P03277 0.3 mmol/kg | Predicted Value of ∆∆QTc at Cmax | 2.23 milliseconds |