Healthy Volunteers, Brain Lesion
Conditions
Brief summary
The primary objective of this study was to evaluate the safety (clinical and biological) and pharmacokinetics (plasma and urine) profile of P03277 following single administration at ascending dose levels in healthy subjects.
Detailed description
This single-center, single ascending dose, phase I/IIa study was divided into 2 parts, involving both healthy subjects and patients with brain lesions: * Study Part I included healthy subjects: double-blind, randomized, placebo control; * Study Part II included patients with brain lesions: open-label. In Part I, the following 6 dosing groups were investigated: * Group 1: 0.025 mmol/kg * Group 2: 0.05 mmol/kg * Group 3: 0.075 mmol/kg * Group 4: 0.1 mmol/kg * Group 5: 0.2 mmol/kg * Group 6: 0.3 mmol/kg Healthy subjects were included and were then administered with P03277 or placebo and were to undergo MRI examination according to the randomization scheme. In Part II, the following 4 doses groups were investigated: * Group 7: 0.05 mmol/kg * Group 8: 0.075 mmol/kg * Group 9: 0.1 mmol/kg * Group 10: 0.2 mmol/kg Patients with brain lesions were included and were then administered with P03277 and underwent MRI examination.
Interventions
DRUGP03277
Part I: P03277 was administered intravenously with a flow rate ranging from 0.5 to 2 mL/s. Part II: P03277 was administered intravenously with a flow rate of 2 mL/s.
DRUGPlacebo
Part I: Placebo was administered intravenously with a flow rate ranging from 0.5 to 2 mL/s. Part II: Placebo was administered intravenously with a flow rate of 2 mL/s.
Sponsors
Guerbet
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Part I: Sequential administration within each group of healthy subjects was established. Part II: The administration to patients within the same day was sequential to ensure the well-being of the patients. At least a 1-hour interval between 2 administrations had to be respected.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Part I: Subjects between 18 and 45 years old (inclusive), with a body mass index (BMI) of 18 to 30 kg/m² (exclusive) and in a good health. * Part II: Patients 18 years old and older and having at least one brain lesion with a disruption of the blood brain barrier (BBB) and/or with abnormal vascularity in the brain. This/these lesion(s) must have been detected by previous imaging evaluation (Computed Tomography or MRI).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter Cmax | From baseline (30 minutes before injection) to 24 hours post-injection | Cmax = maximum concentration measured. Blood samples were taken to assess the P03277 concentration. |
| PK Parameter T1/2 | From baseline (30 minutes before injection) to 24 hours post-injection | T1/2 = terminal elimination half-life of the compound. Blood samples were taken to assess the P03277 concentration. |
| PK Parameter Cl | From baseline (30 minutes before injection) to 24 hours post-injection | Cl = total clearance. Blood samples were taken to assess the P03277 concentration. |
| PK Parameter Vd | From baseline (30 minutes before injection) to 24 hours post-injection | Vd = volume of distribution. Blood samples were taken to assess the P03277 concentration. |
Countries
Belgium
Participant flow
Pre-assignment details
For part I, all patients who were not randomized were screening failures. For part II, all patients who were not allocated to a dose of P03277 were screening failures.
Participants by arm
| Arm | Count |
|---|---|
| Part I (Phase I) P03277 0.025 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.025 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) P03277 0.05 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.05 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) P03277 0.075 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.075 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) P03277 0.1 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.1 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) P03277 0.2 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.2 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) P03277 0.3 mmol/kg 6 subjects received P03277 in one single administration.
P03277 was administered intravenously at 0.3 mmol/kg with a flow rate ranging from 0.5 to 2 mL/s. | 6 |
| Part I (Phase I) Placebo 3 healthy subjects per dose group received placebo in one single administration.
Placebo was administered intravenously with a flow rate ranging from 0.5 to 2 mL/s. | 18 |
| Part II (Phase IIA) P03277 0.05 mmol/kg 3 patients received one single administration of P03277.
P03277 was administered intravenously at 0.05 mmol/kg with a flow rate of 2 mL/s. | 3 |
| Part II (Phase IIA) P03277 0.075 mmol/kg 3 patients received one single administration of P03277.
P03277 was administered intravenously at 0.075 mmol/kg with a flow rate of 2 mL/s. | 3 |
| Part II (Phase IIA) P03277 0.1 mmol/kg 3 patients received one single administration of P03277.
P03277 was administered intravenously at 0.1 mmol/kg with a flow rate of 2 mL/s. | 3 |
| Part II (Phase IIA) P03277 0.2 mmol/kg 3 patients received one single administration of P03277.
P03277 was administered intravenously at 0.2 mmol/kg with a flow rate of 2 mL/s. | 3 |
| Total | 66 |
Baseline characteristics
| Characteristic | Part I (Phase I) P03277 0.025 mmol/kg | Part I (Phase I) P03277 0.05 mmol/kg | Part I (Phase I) P03277 0.075 mmol/kg | Part I (Phase I) P03277 0.1 mmol/kg | Part I (Phase I) P03277 0.2 mmol/kg | Part I (Phase I) P03277 0.3 mmol/kg | Part I (Phase I) Placebo | Part II (Phase IIA) P03277 0.05 mmol/kg | Part II (Phase IIA) P03277 0.075 mmol/kg | Part II (Phase IIA) P03277 0.1 mmol/kg | Part II (Phase IIA) P03277 0.2 mmol/kg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 26.0 years | 25.5 years | 27.5 years | 25.5 years | 23.0 years | 33.5 years | 26.5 years | 40.0 years | 56.0 years | 56.0 years | 53.0 years | 28.0 years |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 8 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 32 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 10 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 34 Participants |
| Weight | 81.65 kg | 71.60 kg | 65.00 kg | 72.50 kg | 69.30 kg | 72.50 kg | 67.90 kg | 87.20 kg | 80.40 kg | 87.20 kg | 85.80 kg | 72.85 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 18 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 2 / 6 | 3 / 6 | 2 / 6 | 4 / 6 | 5 / 6 | 3 / 6 | 11 / 18 | 1 / 3 | 1 / 3 | 1 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 18 | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter Cmax
Cmax = maximum concentration measured. Blood samples were taken to assess the P03277 concentration.
Time frame: From baseline (30 minutes before injection) to 24 hours post-injection
Population: In part I, one patient from the 0.025 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect volume of P03277 injected).~In part II, one patient from the 0.1 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect route of administration, high probability of extravasation).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I (Phase I) P03277 0.025 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 248.7 µg/mL | Standard Deviation 54.5 |
| Part I (Phase I) P03277 0.05 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 524.5 µg/mL | Standard Deviation 69.9 |
| Part I (Phase I) P03277 0.075 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 698.7 µg/mL | Standard Deviation 378.9 |
| Part I (Phase I) P03277 0.1 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 992.0 µg/mL | Standard Deviation 233.1 |
| Part I (Phase I) P03277 0.2 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 2097.6 µg/mL | Standard Deviation 572.3 |
| Part I (Phase I) P03277 0.3 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 3916.4 µg/mL | Standard Deviation 1114.8 |
| Part II (Phase IIA) 0.05 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 370.8 µg/mL | Standard Deviation 117.6 |
| Part II (Phase IIA) 0.075 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 618.2 µg/mL | Standard Deviation 439.7 |
| Part II (Phase IIA) 0.1 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 701.6 µg/mL | Standard Deviation 48.5 |
| Part II (Phase IIA) 0.2 mmol/kg | Pharmacokinetic (PK) Parameter Cmax | 1434.9 µg/mL | Standard Deviation 651.5 |
Primary
PK Parameter Cl
Cl = total clearance. Blood samples were taken to assess the P03277 concentration.
Time frame: From baseline (30 minutes before injection) to 24 hours post-injection
Population: In part I, one patient from the 0.025 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect volume of P03277 injected).~In part II, one patient from the 0.1 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect route of administration, high probability of extravasation).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I (Phase I) P03277 0.025 mmol/kg | PK Parameter Cl | 91.7 mL/min | Standard Deviation 8.5 |
| Part I (Phase I) P03277 0.05 mmol/kg | PK Parameter Cl | 100.1 mL/min | Standard Deviation 9.5 |
| Part I (Phase I) P03277 0.075 mmol/kg | PK Parameter Cl | 106.4 mL/min | Standard Deviation 20.7 |
| Part I (Phase I) P03277 0.1 mmol/kg | PK Parameter Cl | 96.1 mL/min | Standard Deviation 11.8 |
| Part I (Phase I) P03277 0.2 mmol/kg | PK Parameter Cl | 101.3 mL/min | Standard Deviation 10.9 |
| Part I (Phase I) P03277 0.3 mmol/kg | PK Parameter Cl | 102.2 mL/min | Standard Deviation 19 |
| Part II (Phase IIA) 0.05 mmol/kg | PK Parameter Cl | 105.3 mL/min | Standard Deviation 13.5 |
| Part II (Phase IIA) 0.075 mmol/kg | PK Parameter Cl | 106.5 mL/min | Standard Deviation 15.7 |
| Part II (Phase IIA) 0.1 mmol/kg | PK Parameter Cl | 108.6 mL/min | Standard Deviation 5 |
| Part II (Phase IIA) 0.2 mmol/kg | PK Parameter Cl | 109.9 mL/min | Standard Deviation 18.2 |
Primary
PK Parameter T1/2
T1/2 = terminal elimination half-life of the compound. Blood samples were taken to assess the P03277 concentration.
Time frame: From baseline (30 minutes before injection) to 24 hours post-injection
Population: In part I, one patient from the 0.025 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect volume of P03277 injected).~In part II, one patient from the 0.1 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect route of administration, high probability of extravasation).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I (Phase I) P03277 0.025 mmol/kg | PK Parameter T1/2 | 1.65 hours | Standard Deviation 0.43 |
| Part I (Phase I) P03277 0.05 mmol/kg | PK Parameter T1/2 | 1.50 hours | Standard Deviation 0.22 |
| Part I (Phase I) P03277 0.075 mmol/kg | PK Parameter T1/2 | 1.58 hours | Standard Deviation 0.3 |
| Part I (Phase I) P03277 0.1 mmol/kg | PK Parameter T1/2 | 1.73 hours | Standard Deviation 0.26 |
| Part I (Phase I) P03277 0.2 mmol/kg | PK Parameter T1/2 | 1.82 hours | Standard Deviation 0.35 |
| Part I (Phase I) P03277 0.3 mmol/kg | PK Parameter T1/2 | 2.09 hours | Standard Deviation 0.15 |
| Part II (Phase IIA) 0.05 mmol/kg | PK Parameter T1/2 | 1.90 hours | Standard Deviation 0.04 |
| Part II (Phase IIA) 0.075 mmol/kg | PK Parameter T1/2 | 2.04 hours | Standard Deviation 0.06 |
| Part II (Phase IIA) 0.1 mmol/kg | PK Parameter T1/2 | 1.79 hours | Standard Deviation 0.17 |
| Part II (Phase IIA) 0.2 mmol/kg | PK Parameter T1/2 | 1.94 hours | Standard Deviation 0.06 |
Primary
PK Parameter Vd
Vd = volume of distribution. Blood samples were taken to assess the P03277 concentration.
Time frame: From baseline (30 minutes before injection) to 24 hours post-injection
Population: In part I, one patient from the 0.025 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect volume of P03277 injected).~In part II, one patient from the 0.1 mmol/kg group was excluded from the pharmacokinetics analysis (incorrect route of administration, high probability of extravasation).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I (Phase I) P03277 0.025 mmol/kg | PK Parameter Vd | 13203 mL | Standard Deviation 4122 |
| Part I (Phase I) P03277 0.05 mmol/kg | PK Parameter Vd | 12945 mL | Standard Deviation 1692 |
| Part I (Phase I) P03277 0.075 mmol/kg | PK Parameter Vd | 14312 mL | Standard Deviation 2742 |
| Part I (Phase I) P03277 0.1 mmol/kg | PK Parameter Vd | 14351 mL | Standard Deviation 2645 |
| Part I (Phase I) P03277 0.2 mmol/kg | PK Parameter Vd | 15922 mL | Standard Deviation 3224 |
| Part I (Phase I) P03277 0.3 mmol/kg | PK Parameter Vd | 18487 mL | Standard Deviation 3575 |
| Part II (Phase IIA) 0.05 mmol/kg | PK Parameter Vd | 17320 mL | Standard Deviation 1942 |
| Part II (Phase IIA) 0.075 mmol/kg | PK Parameter Vd | 18796 mL | Standard Deviation 2478 |
| Part II (Phase IIA) 0.1 mmol/kg | PK Parameter Vd | 16823 mL | Standard Deviation 804 |
| Part II (Phase IIA) 0.2 mmol/kg | PK Parameter Vd | 18355 mL | Standard Deviation 2522 |