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

• ClinicalTrials.gov Identifier: NCT02411201
• Recruitment Status: Completed
• First Posted: April 8, 2015
• Results First Posted: March 9, 2017
• Last Update Posted: March 9, 2017
• Sponsor: Guerbet
• Information provided by (Responsible Party): Guerbet

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Magnetic Resonance Imaging	Drug: DOTAREM	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: DOTAREM® Pharmacokinetics, Safety and Efficacy Study in Pediatric Subjects Aged <2 Years (Term Newborn Infants to Toddlers 23 Months of Age Inclusive)
• Study Start Date: March 2015
• Actual Primary Completion Date: October 2015
• Actual Study Completion Date: October 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: DOTAREM	Drug: DOTAREM; Single intravenous injection of 0.1 mmol/kg body weight; Other Name: gadoterate meglumine

Outcome Measures

Primary Outcome Measures :

1. Area Under the Curve of DOTAREM in Plasma [ 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 ]
   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.
2. Rate Constant of the Terminal Phase of DOTAREM [ 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 ]
   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.
3. Terminal Elimination Half-life of DOTAREM From Plasma [ 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 ]
   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.
4. Total Clearance of DOTAREM From Plasma [ 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 ]
   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.
5. Volume of Distribution of DOTAREM at Steady State [ 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 ]
   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.

Secondary Outcome Measures :

1. Simulated Plasma Concentration of DOTAREM [ Time Frame: 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.
2. MRI Lesion Visualization at Subject Level [ Time Frame: 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)

Eligibility Criteria

• Ages Eligible for Study: up to 2 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Austria

Landes-Frauen-und Kinderklinik Linz

Linz, Austria, 4020

France

CHU

Bordeaux, France, 33604

CHRU

Lille, France, 59037

Hôpital de Hautepierre

Strasbourg, France, 67098

Hungary

Department of Molecular and Neurological Clinical and Research Center

Budapest, Hungary, 1083

University of Debrecen Medical Center

Debrecen, Hungary, 4032

Borsod-Abaúj-Zemplén University County Hospital

Miskolc, Hungary, 3526

Poland

Uniwersytecki Szpital Dziecięcy w Lublinie

Lublin, Poland, 20093

Instytut Pomnik -Centrum Zdrowia Dziecka

Warszawa, Poland, 04730

Sponsors and Collaborators

Guerbet

Investigators

• Study Director: Project Manager; Guerbet

More Information

• Responsible Party: Guerbet
• ClinicalTrials.gov Identifier: NCT02411201
• Other Study ID Numbers: DGD-44-063; 2013-003215-21 ( EudraCT Number )
• First Posted: April 8, 2015
• Results First Posted: March 9, 2017
• Last Update Posted: March 9, 2017
• Last Verified: January 2017

Additional relevant MeSH terms:

Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action