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

• Sponsor: Guerbet (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02411201
• Collaborator: (none)
• Enrollment: 51
• Locations: 9
• Arm: 1
• Duration (Months): 7
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.8

Study Details

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
• 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: Mar 1, 2015
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Secondary Outcome Measures

1. 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.

2. 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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 2 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Landes-Frauen-und Kinderklinik Linz	Linz		Austria	4020
2	CHU	Bordeaux		France	33604
3	CHRU	Lille		France	59037
4	Hôpital de Hautepierre	Strasbourg		France	67098
5	Department of Molecular and Neurological Clinical and Research Center	Budapest		Hungary	1083
6	University of Debrecen Medical Center	Debrecen		Hungary	4032
7	Borsod-Abaúj-Zemplén University County Hospital	Miskolc		Hungary	3526
8	Uniwersytecki Szpital Dziecięcy w Lublinie	Lublin		Poland	20093
9	Instytut Pomnik -Centrum Zdrowia Dziecka	Warszawa		Poland	04730

Sponsors and Collaborators

• Guerbet

Investigators

• Study Director: Project Manager, Guerbet

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Guerbet
• ClinicalTrials.gov Identifier: NCT02411201
• Other Study ID Numbers: DGD-44-063; 2013-003215-21
• First Posted: Apr 8, 2015
• Last Update Posted: Mar 9, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate

Study Results

Participant Flow

Recruitment Details	A total of 51 children aged less than 2 years were recruited in 4 countries: Austria, France, Hungary and Poland.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Period Title: Overall Study
STARTED	51
COMPLETED	45
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Overall Participants	45
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	9.9 (7.4)
Age, Customized (Count of Participants)
<1 month	5 11.1%
1 to 3 months	9 20%
>3 months to <24 months	31 68.9%
Sex: Female, Male (Count of Participants)
Female	23 51.1%
Male	22 48.9%
Region of Enrollment (participants) [Number]
Austria	3 6.7%
Hungary	9 20%
Poland	29 64.4%
France	4 8.9%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve of DOTAREM in Plasma
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Median (Full Range) [hour.µmol/L]	1591.1

2. Primary Outcome

Title	Rate Constant of the Terminal Phase of DOTAREM
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Median (Full Range) [hour-1]	0.5117

3. Primary Outcome

Title	Terminal Elimination Half-life of DOTAREM From Plasma
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Mean (Full Range) [hour]	1.3545

4. Primary Outcome

Title	Total Clearance of DOTAREM From Plasma
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Mean (Full Range) [L/hour per kg]	0.0602

5. Primary Outcome

Title	Volume of Distribution of DOTAREM at Steady State
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Mean (Full Range) [L/kg]	0.0473

6. Secondary Outcome

Title	Simulated Plasma Concentration of DOTAREM
Description	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

Outcome Measure Data

Analysis Population Description

Among the 45 subjects who received one injection of DOTAREM, all had at least one blood sample available for pharmacokinetics.

Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
Measure Participants	45
Simulated concentration at 10 min	320.92
Simulated concentration at 20 min	275.67

7. Secondary Outcome

Title	MRI Lesion Visualization at Subject Level
Description	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)

Outcome Measure Data

Analysis Population Description

Lesion visualization was evaluated in 28 subjects who underwent contrast-enhanced MRI for central nervous system indication.

Arm/Group Title	Pre-contrast	Pre- + Post-contrast
Arm/Group Description	Lesion visualization was assessed before DOTAREM injection	Lesion visualization was assessed after DOTAREM injection
Measure Participants	28	28
Sum of scores of lesion border delineation	4.3 (3.7)	5.1 (4.0)
Sum of scores of internal morphology	4.3 (3.9)	5.2 (4.3)
Sum of scores of contrast enhancement	1.9 (1.5)	5.0 (4.5)

Adverse Events

Time Frame	Adverse Events were collected from informed consent signature to the end of the study (7+/-1 day after DOTAREM administration)
Arm/Group Title	DOTAREM
Arm/Group Description	Subjects receiving a single intravenous injection of 0.1 mmol/kg body weight of DOTAREM
All Cause Mortality
	DOTAREM
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	DOTAREM
	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)
Blood and lymphatic system disorders
Anaemia	1/45 (2.2%)	1
General disorders
Pyrexia	1/45 (2.2%)	1
Infections and infestations
Upper respiratory tract infection	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	DOTAREM
	Affected / at Risk (%)	# Events
Total	12/45 (26.7%)
Blood and lymphatic system disorders
Leukopenia	2/45 (4.4%)	2
Thrombocytopenia	1/45 (2.2%)	1
Gastrointestinal disorders
Abdominal pain	1/45 (2.2%)	1
Diarrhoea	1/45 (2.2%)	1
Vomiting	1/45 (2.2%)	1
Nausea	1/45 (2.2%)	1
General disorders
Pyrexia	5/45 (11.1%)	5
Device difficult to use	1/45 (2.2%)	1
Fatigue	1/45 (2.2%)	1
Infections and infestations
Bronchitis	1/45 (2.2%)	1
Infection	1/45 (2.2%)	1
Nasopharyngitis	1/45 (2.2%)	1
Rhinitis	1/45 (2.2%)	1
Tonsillitis	1/45 (2.2%)	1
Urinary tract infection	1/45 (2.2%)	1
Nervous system disorders
Tremor	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Rash	1/45 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All written or oral papers and publications must have the joint agreement of the investigator and Guerbet. The Investigator shall not use the sponsor's name in any publication without the prior permission of Guerbet. Each investigator agrees not to publish/present the evaluation of the main criterion involving only the patients he/she has included. Any abstract project will be first submitted to Guerbet at least 10 working days before submission to the congress scientific committee.