Central Nervous System Diseases, Pediatric Disorder, Body Indication
Conditions
Brief summary
This Phase II open-label, uncontrolled, multicenter trial is designed to investigate the pharmacokinetic (PK) profile of gadopiclenol in plasma, in pediatric patients aged up to 23 months inclusive (term neonates or preterm infants after the neonatal period), using a population PK approach. Primary objective is to evaluate the PK profile of gadopiclenol in plasma following single intravenous injection of 0.05 mmol/kg body weight (BW) in pediatric population aged up to 23 months (inclusive) scheduled for a contrast-enhanced MRI examination of any body region including central nervous system (CNS).
Detailed description
Three age groups are defined: * Group 1: patients aged 3 to 23 months (inclusive) * Group 2: patients aged 28 days to less than 3 months; * Group 3: patients aged from birth to 27 days (term newborns). At study set-up, the inclusions started with the oldest patients in group 1 and using an age-down staggered approach. The decision to start the inclusions in group 2 was taken by the Trial Safety Review Board based on safety assessment over one-day period after injection of the first 13 patients in group 1. According to the protocol version 4 (amendments 2 & 3), the age-down staggered approach was discontinued to allow the inclusions in Group 3 (patients aged from birth to 27 days), simultaneously to inclusions in group 1 and group 2. A total of 3 blood samples per patient were taken post-injection for PK analysis.
Interventions
DRUGGadopiclenol
Patients will receive a single dose of gadopiclenol calculated according to their BW on the day of MRI examination. Gadopiclenol will be administered at a dose of 0.05 mmol/kg BW (0.1 mL/kg BW).
Sponsors
Guerbet
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 23 Months
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Female or male pediatric patient aged from birth to 23 months of age inclusive (term neonates for all age groups or preterm infants after the neonatal period for groups 1 or 2). The neonatal period for preterm newborns is defined as the day of birth through the expected date of delivery plus 27 days. Term is defined as ≥37 completed weeks of amenorrhea, 2. Patient with known or highly suspected abnormalities/ lesion(s), scheduled to undergo contrast-enhanced MRI of any body region including CNS \[...\] Main
Exclusion criteria
1. Patient planned for treatment or procedure (e.g. surgery) that would prevent from obtaining the required blood samples or performing other trial procedures between the screening visit and up to one day after gadopiclenol administration, 2. Patient undergoing treatment or procedure (e.g., diuretics, clinically significant blood loss or blood transfusion) preceding or subsequent to gadopiclenol administration that would alter gadopiclenol pharmacokinetic parameters, 3. Patient with acute or chronic renal insufficiency defined as estimated Glomerular Filtration Rate (eGFR) out of age-adjusted normal value calculated based on bedside Schwartz equation, \[...\] 9\. Patient undergoing a change in chemotherapy (product or dosage) within one day prior to or one day after gadopiclenol administration, 10. Patient who received or will receive any other contrast agent for CT and/or MRI within one week prior to or one week after gadopiclenol administration, 11. Patient with contraindication for MRI such as iron metal implants (e.g., aneurysm clips, pacemaker), 12. Patient with history of anaphylactoid or anaphylactic reaction to any allergen including drugs and contrast agents \[...\]
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUCinf) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours) | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Elimination Half-life (t1/2α) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Terminal Half-life (t1/2β) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Gadopiclenol Concentrations 10 Min Post-injection (C10 Min) | blood sample collection 10 minutes post-injection of gadopiclenol for analysis | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Gadopiclenol Concentration 20 Min Post-injection (C20 Min) | blood sample collection 20 minutes post-injection of gadopiclenol | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Gadopiclenol Concentrations 30 Min Post-injection (C30 Min) | blood sample collection 30 minutes post-injection of gadopiclenol | Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg |
| Clearance | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Individual predicted final model parameter scaled by body weight |
| Central Volume of Distribution (V1) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Individual predicted final model parameter scaled by body weight |
| Inter-compartment Clearance (Q) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Individual predicted final model parameter scaled by body weight |
| Peripheral Volume of Distribution (V2) | A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours). | Individual predicted final model parameter scaled by body weight |
Countries
Hungary, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Age Group 1: Patients Aged 3 to 23 Months One Investigational Medicinal Product (IMP) dose of 0.05 mmol/kg was injected in all patients.
Gadopiclenol: Patients received a single dose of gadopiclenol calculated according to their BW on the day of MRI examination. Gadopiclenol was administered at a dose of 0.05 mmol/kg BW (0.1 mL/kg BW). | 33 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months One Investigational Medicinal Product (IMP) dose of 0.05 mmol/kg was injected in all patients.
Gadopiclenol: Patients received a single dose of gadopiclenol calculated according to their BW on the day of MRI examination. Gadopiclenol was administered at a dose of 0.05 mmol/kg BW (0.1 mL/kg BW). | 2 |
| Age Group 3: Patients Aged From Birth to 27 Days (Term Newborns) One Investigational Medicinal Product (IMP) dose of 0.05 mmol/kg was injected in all patients.
Gadopiclenol: Patients received a single dose of gadopiclenol calculated according to their BW on the day of MRI examination. Gadopiclenol was administered at a dose of 0.05 mmol/kg BW (0.1 mL/kg BW). | 1 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Age Group 3: Patients Aged From Birth to 27 Days (Term Newborns) | Age Group 1: Patients Aged 3 to 23 Months | Total |
|---|---|---|---|---|
| Age, Continuous | 1.94 months STANDARD_DEVIATION 0.14 | 0.8 months | 13.11 months STANDARD_DEVIATION 6.22 | 12.15 months STANDARD_DEVIATION 6.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 32 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 33 Participants | 36 Participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 10 participants | 12 participants |
| Region of Enrollment Poland | 0 participants | 0 participants | 19 participants | 19 participants |
| Region of Enrollment United States | 1 participants | 0 participants | 4 participants | 5 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 16 Participants | 18 Participants |
| Weight | 5.10 kilogram STANDARD_DEVIATION 0.28 | 4.50 kilogram | 9.40 kilogram STANDARD_DEVIATION 2.18 | 9.03 kilogram STANDARD_DEVIATION 2.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 13 / 33 | 2 / 2 | 0 / 1 |
| serious Total, serious adverse events | 8 / 33 | 0 / 2 | 0 / 1 |
Outcome results
Primary
Area Under the Curve (AUCinf)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours)
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Area Under the Curve (AUCinf) | 392.3 h.mg/L | Geometric Coefficient of Variation 27.6 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Area Under the Curve (AUCinf) | 493.3 h.mg/L | Geometric Coefficient of Variation 9.9 |
Primary
Central Volume of Distribution (V1)
Individual predicted final model parameter scaled by body weight
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Central Volume of Distribution (V1) | 0.176 L/kg | Standard Deviation 0.033 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Central Volume of Distribution (V1) | 0.214 L/kg | Standard Deviation 0.03 |
Primary
Clearance
Individual predicted final model parameter scaled by body weight
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Clearance | 0.128 L/h/kg | Standard Deviation 0.035 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Clearance | 0.097 L/h/kg | Standard Deviation 0.004 |
Primary
Elimination Half-life (t1/2α)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Elimination Half-life (t1/2α) | 0.3 h | Geometric Coefficient of Variation 30.3 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Elimination Half-life (t1/2α) | 0.3 h | Geometric Coefficient of Variation 30.3 |
Primary
Gadopiclenol Concentration 20 Min Post-injection (C20 Min)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: blood sample collection 20 minutes post-injection of gadopiclenol
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Gadopiclenol Concentration 20 Min Post-injection (C20 Min) | 161.5 mg/L | Geometric Coefficient of Variation 17.2 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Gadopiclenol Concentration 20 Min Post-injection (C20 Min) | 149.8 mg/L | Geometric Coefficient of Variation 13.4 |
Primary
Gadopiclenol Concentrations 10 Min Post-injection (C10 Min)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: blood sample collection 10 minutes post-injection of gadopiclenol for analysis
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Gadopiclenol Concentrations 10 Min Post-injection (C10 Min) | 226.8 mg/L | Geometric Coefficient of Variation 15.8 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Gadopiclenol Concentrations 10 Min Post-injection (C10 Min) | 190.4 mg/L | Geometric Coefficient of Variation 16.2 |
Primary
Gadopiclenol Concentrations 30 Min Post-injection (C30 Min)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: blood sample collection 30 minutes post-injection of gadopiclenol
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Gadopiclenol Concentrations 30 Min Post-injection (C30 Min) | 109.4 mg/L | Geometric Coefficient of Variation 22.4 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Gadopiclenol Concentrations 30 Min Post-injection (C30 Min) | 116.2 mg/L | Geometric Coefficient of Variation 13.3 |
Primary
Inter-compartment Clearance (Q)
Individual predicted final model parameter scaled by body weight
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Inter-compartment Clearance (Q) | 0.099 L/h/kg | Standard Deviation 0.025 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Inter-compartment Clearance (Q) | 0.123 L/h/kg | Standard Deviation 0.029 |
Primary
Peripheral Volume of Distribution (V2)
Individual predicted final model parameter scaled by body weight
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Peripheral Volume of Distribution (V2) | 0.066 L/kg | Standard Deviation 0.014 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Peripheral Volume of Distribution (V2) | 0.066 L/kg | Standard Deviation 0.003 |
Primary
Terminal Half-life (t1/2β)
Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol at a dose of 0.05 mmol/kg
Time frame: A total of 3 blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 minutes, 2-4 hours and 6-8 hours).
Population: Among the 36 patients who received an injection of gadopiclenol for MRI (Safety Set), the patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation impacting the popPK model, therefore 35 patients were included in the population PK analysis including 33 patients aged 3-23 months and 2 patients aged 28-89 days.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Group 1: Patients Aged 3 to 23 Months | Terminal Half-life (t1/2β) | 1.5 h | Geometric Coefficient of Variation 21.4 |
| Age Group 2: Patients Aged 28 Days to Less Than 3 Months | Terminal Half-life (t1/2β) | 2.1 h | Geometric Coefficient of Variation 8.4 |