Magnetic Resonance Imaging
Conditions
Brief summary
The main purpose of the study is to evaluate the pharmacokinetics of DOTAREM® in the body of children aged less than 2 years thanks to several blood samples (3 ml in total) taken following the administration of DOTAREM®. DOTAREM® is a contrast agent commonly used for enhancement of Magnetic Resonance Imaging (MRI) to potentially improve the quality of the images and help the diagnosis. Children aged less than 2 years scheduled to undergo routine gadolinium-enhanced MRI of any body region may take part in the study. In this case they will receive DOTAREM®, a solution injected at the standard dose of 0.2mL/kg (0.1 mmol/kg) of body weight.
Interventions
DRUGDOTAREM
Single intravenous injection of 0.1 mmol/kg body weight
Sponsors
Guerbet
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 2 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric subject aged \<2 years (term newborn infants to toddlers 23 months of age inclusive). Term is defined as ≥37 weeks of amenorrhea * Subject is scheduled to undergo routine gadolinium-enhanced MRI of any body region (e.g. CNS, cardiac) at the dose of 0.1 mmol/kg BW (0.2 mL/kg BW) * Subject with normal renal function for its age, estimated glomerular filtration rate calculated based on the Schwartz formula
Exclusion criteria
* Subject planned for intervention (e.g. surgery) between the screening visit and up to 24 hours after DOTAREM injection * Subject whose preceding or subsequent treatment to DOTAREM injection (e.g., blood loss or receiving blood, treatment with diuretics, etc…) would alter DOTAREM pharmacokinetics parameters * Subject with subsequent planned treatment after DOTAREM injection that would prevent obtaining the required blood samples (e.g., emergency surgery, etc…) * Subject with a history of a bleeding disorder * Subject with severe liver disease (Child's Pugh Classification B or greater or serum direct bilirubin greater than 0.3 mg/dL, age adjusted) * Subject with electrolyte or fluid imbalance that presents undue risk * Subject undergoing a change in chemotherapy within 48 hours prior to and up to 24 hours after DOTAREM injection * Subject who received or will receive any other contrast agent within 72 hours prior to DOTAREM injection or up to 24 hours after DOTAREM injection * Subject with contraindication for MRI such as iron metal implants (e.g. aneurysm clips) * Subject with history of anaphylactoid or anaphylactic reaction to any allergen including drugs and contrast agents * Subject having participated within 30 days in a clinical study involving an investigational drug or device * Subject planned to participate simultaneously to another clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate Constant of the Terminal Phase of DOTAREM | Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Rate constant of the terminal phase was determined from typical and individual DOTAREM concentration-time profiles. |
| Total Clearance of DOTAREM From Plasma | Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Total clearance was determined from typical and individual DOTAREM concentration-time profiles. |
| Volume of Distribution of DOTAREM at Steady State | Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Volume of distribution at steady state was determined from typical and individual DOTAREM concentration-time profiles. |
| Area Under the Curve of DOTAREM in Plasma | Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Area under the curve was determined from typical and individual DOTAREM concentration-time profiles. |
| Terminal Elimination Half-life of DOTAREM From Plasma | Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Terminal elimination half-life was determined from typical and individual DOTAREM concentration-time profiles. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MRI Lesion Visualization at Subject Level | Pre-injection and post-injection (estimated between 5 and 20 minutes after injection) | Lesion visualization was assessed on up to five most representative lesions per subject based on scoring of 3 co-endpoints: * border delineation (based on a 3-point scale where 1=none; 2=moderate and 3=clear and complete) * internal morphology (based on a 3-point scale where 1=poorly visible; 2=moderately visible and 3=sufficiently visible) * contrast enhancement (based on a 3-point scale where 1=none; 2=weak and 3=clear and bright) For each co-endpoint, a sum of scores was calculated at subject level as follows: sum of scores = score of the lesion 1 (+ score of the lesion 2 + score of the lesion 3 + score of the lesion 4 + score of the lesion 5, when applicable) |
| Simulated Plasma Concentration of DOTAREM | at 10 and 20 min post-injection | Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. |
Countries
Austria, France, Hungary, Poland
Participant flow
Recruitment details
A total of 51 children aged less than 2 years were recruited in 4 countries: Austria, France, Hungary and Poland.
Participants by arm
| Arm | Count |
|---|---|
| DOTAREM Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Age group completed | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | DOTAREM |
|---|---|
| Age, Continuous | 9.9 months STANDARD_DEVIATION 7.4 |
| Age, Customized <1 month | 5 Participants |
| Age, Customized 1 to 3 months | 9 Participants |
| Age, Customized >3 months to <24 months | 31 Participants |
| Region of Enrollment Austria | 3 participants |
| Region of Enrollment France | 4 participants |
| Region of Enrollment Hungary | 9 participants |
| Region of Enrollment Poland | 29 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 45 |
| serious Total, serious adverse events | 1 / 45 |
Outcome results
Primary
Area Under the Curve of DOTAREM in Plasma
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Area under the curve was determined from typical and individual DOTAREM concentration-time profiles.
Time frame: Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOTAREM | Area Under the Curve of DOTAREM in Plasma | 1591.1 hour.µmol/L |
Primary
Rate Constant of the Terminal Phase of DOTAREM
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Rate constant of the terminal phase was determined from typical and individual DOTAREM concentration-time profiles.
Time frame: Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DOTAREM | Rate Constant of the Terminal Phase of DOTAREM | 0.5117 hour-1 |
Primary
Terminal Elimination Half-life of DOTAREM From Plasma
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Terminal elimination half-life was determined from typical and individual DOTAREM concentration-time profiles.
Time frame: Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DOTAREM | Terminal Elimination Half-life of DOTAREM From Plasma | 1.3545 hour |
Primary
Total Clearance of DOTAREM From Plasma
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Total clearance was determined from typical and individual DOTAREM concentration-time profiles.
Time frame: Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DOTAREM | Total Clearance of DOTAREM From Plasma | 0.0602 L/hour per kg |
Primary
Volume of Distribution of DOTAREM at Steady State
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method. Volume of distribution at steady state was determined from typical and individual DOTAREM concentration-time profiles.
Time frame: Blood samples were collected during 3 time windows: 15 min to 60 min, 2 hours to 4 hours and 6 hours to 8 hours post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DOTAREM | Volume of Distribution of DOTAREM at Steady State | 0.0473 L/kg |
Secondary
MRI Lesion Visualization at Subject Level
Lesion visualization was assessed on up to five most representative lesions per subject based on scoring of 3 co-endpoints: * border delineation (based on a 3-point scale where 1=none; 2=moderate and 3=clear and complete) * internal morphology (based on a 3-point scale where 1=poorly visible; 2=moderately visible and 3=sufficiently visible) * contrast enhancement (based on a 3-point scale where 1=none; 2=weak and 3=clear and bright) For each co-endpoint, a sum of scores was calculated at subject level as follows: sum of scores = score of the lesion 1 (+ score of the lesion 2 + score of the lesion 3 + score of the lesion 4 + score of the lesion 5, when applicable)
Time frame: Pre-injection and post-injection (estimated between 5 and 20 minutes after injection)
Population: Lesion visualization was evaluated in 28 subjects who underwent contrast-enhanced MRI for central nervous system indication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DOTAREM | MRI Lesion Visualization at Subject Level | Sum of scores of lesion border delineation | 4.3 units on a scale | Standard Deviation 3.7 |
| DOTAREM | MRI Lesion Visualization at Subject Level | Sum of scores of internal morphology | 4.3 units on a scale | Standard Deviation 3.9 |
| DOTAREM | MRI Lesion Visualization at Subject Level | Sum of scores of contrast enhancement | 1.9 units on a scale | Standard Deviation 1.5 |
| Pre- + Post-contrast | MRI Lesion Visualization at Subject Level | Sum of scores of lesion border delineation | 5.1 units on a scale | Standard Deviation 4 |
| Pre- + Post-contrast | MRI Lesion Visualization at Subject Level | Sum of scores of internal morphology | 5.2 units on a scale | Standard Deviation 4.3 |
| Pre- + Post-contrast | MRI Lesion Visualization at Subject Level | Sum of scores of contrast enhancement | 5.0 units on a scale | Standard Deviation 4.5 |
Secondary
Simulated Plasma Concentration of DOTAREM
Pharmacokinetics interpretation was performed using a pharmacokinetic population modelling approach. DOTAREM concentrations in plasma were analyzed using a validated LC-MS/MS method.
Time frame: at 10 and 20 min post-injection
Population: Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DOTAREM | Simulated Plasma Concentration of DOTAREM | Simulated concentration at 20 min | 275.67 µmol/L |
| DOTAREM | Simulated Plasma Concentration of DOTAREM | Simulated concentration at 10 min | 320.92 µmol/L |