DOTAREM Pharmacokinetics and Safety Study in Pediatric Subjects Aged < 2 Years

Study Overview
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Brief Summary
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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.

Official Title
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DOTAREM® Pharmacokinetics, Safety and Efficacy Study in Pediatric Subjects Aged <2 Years (Term Newborn Infants to Toddlers 23 Months of Age Inclusive)

Conditions
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Magnetic Resonance Imaging

Intervention / Treatment
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* Drug: DOTAREM


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DOTAREM<br> | Drug: DOTAREM<br>* Single intravenous injection of 0.1 mmol/kg body weight<br>* Other names: gadoterate meglumine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | at 10 and 20 min post-injection | 
| 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) | Pre-injection and post-injection (estimated between 5 and 20 minutes after injection) |