Effect On Body Movement And Mental Skills In Patients Who Received Gadolinium-based Contrast Media For Magnetic Resonance Examination Multiple Times Within 5 Years

Study Overview

Effect on Body Movement and Mental Skills in Patients Who Received Gadolinium-based Contrast Media for Magnetic Resonance Examination Multiple Times Within 5 Years

This study is a postmarketing requirement jointly carried out by four NDA holders (Bayer AG, Bracco, GE Healthcare and Guerbet) and the CRO IQVIA. The study aims to create detailed images of the organs and tissue of the human body during x-ray, CT-scan or MRI investigations, doctors are using contrast media (a kind of dye) which can be given to patients by injection into a blood vessel or by mouth. In this study researchers want to find out whether so called gadolinium-based contrast agents (GBCAs) have an effect on body movement and mental skills when given to participants multiple times within 5 years. The study plans to enroll about 2076 participants suffering from a condition for which they are likely to have at least annually a MRI or another imaging examinations. Only adults up to 65 years will be considered to join this study. During the study duration of 5 years participants will receive annually a MRI or other imaging tests (such as CT-scan, x-ray) and will visit the study doctor at least 7 times for physical examinations, laboratory investigations and tests on body movement and mental skills.

The primary objective of the study is to assess the potential effect of repeated exposure to either a linear or a macrocyclic gadolinium-based contrast agent (GBCA) on change from baseline to Year 5 in composite measure of motor and cognitive function among neurologically normal adults in comparison to a matched non-GBCA- exposed control group. The secondary objectives comprise the assessment of the following endpoints in GBCA-exposed participants as compared to controls a) changes from baseline in composite measure of motor and cognitive function post-baseline on yearly basis (Years 1 to 4); b) changes from baseline in each individual test of motor and cognitive function on yearly basis (Years 1 to 5). Total Gd concentrations in blood and urine samples on yearly basis (Years 1 to 5) and adverse events will be collected as secondary objectives. Of note : The study is considered interventional because of the addition of UE-MRI scans for all participants, as well as blood sampling and the administration of the motor and cognitive tests. The GBCA administered as part of the contrast-enhanced MR imaging in the experimental arms is not the intervention in this study. Neither the protocol nor the investigators assign patients to a specific GBCA as part of the study, making this part of the study observational rather than interventional. The participants were already scheduled, prior to study screening, to undergo CE-MRI as part of their clinical care. The choice of GBCA for the CE-MRI will be based on medical need and institutional usage of GBCA, independent of study participation.

Motor Function
Cognitive Function
Contrast Media

PROCEDURE: Motor Tests
PROCEDURE: Cognitive Tests
PROCEDURE: Unenhanced-MRI of the brain
PROCEDURE: Gadolinium Measurements
DRUG: Gadoxetate disodium
DRUG: Gadobenate dimeglumine
DRUG: Gadodiamide
DRUG: Gadoterate meglumine
DRUG: Gadobutrol
DRUG: Gadoteridol

DGD-44-065
20405 (OTHER Identifier) (OTHER: Bayer)
GMRA-105 (OTHER Identifier) (OTHER: Bracco)
GE-041-081 (OTHER Identifier) (OTHER: GE Healthcare)
IQVIA-ODYS-001-LZA45541 (OTHER Identifier) (OTHER: IQVIA)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-04-30	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-05-15
First Submitted that Met QC Criteria 2020-04-30	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-05-17
First Posted (ACTUAL) 2020-05-04	Results First Posted N/A	Last Verified 2024-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Other

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Linear GBCAs Adult participants, who were scheduled for repeated enhanced magnetic resonance imaging (MRI), receive a linear gadoliniumbased contrast agent (GBCA, i.e. Eovist/ Primovist, MultiHance or Omniscan) prior to MRI. Each participant will receive the same GBCA	PROCEDURE: Motor Tests To assess motor function annually PROCEDURE: Cognitive Tests To assess cognitive function annually PROCEDURE: Unenhanced-MRI of the brain The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality PROCEDURE: Gadolinium Measurements Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration DRUG: Gadoxetate disodium Administered as defined by the treating physician as part of routine clinical practice DRUG: Gadobenate dimeglumine Administered as defined by the treating physician as part of routine clinical practice DRUG: Gadodiamide Administered as defined by the treating physician as part of routine clinical practice
EXPERIMENTAL: Macrocyclic GBCAs Adult participants, who were scheduled for repeated enhanced magnetic resonance imaging (MRI), receive a macrocyclic gadolinium-based contrast agent (GBCA, i.e. Gadavist/ Gadovist, Dotarem, Magnescope or ProHance) prior to MRI. Each participant will recei	PROCEDURE: Motor Tests To assess motor function annually PROCEDURE: Cognitive Tests To assess cognitive function annually PROCEDURE: Unenhanced-MRI of the brain The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality PROCEDURE: Gadolinium Measurements Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration DRUG: Gadoterate meglumine Administered as defined by the treating physician as part of routine clinical practice DRUG: Gadobutrol Administered as defined by the treating physician as part of routine clinical practice DRUG: Gadoteridol Administered as defined by the treating physician as part of routine clinical practice
OTHER: No GBCA (Control arm) Adult participants who were never exposed to any gadolinium-based contrast agent and matching the population characteristics of the two GBCA arms. They will not receive any gadolinium-based contrast agent over the study course, but may undergo clinically	PROCEDURE: Motor Tests To assess motor function annually PROCEDURE: Cognitive Tests To assess cognitive function annually PROCEDURE: Unenhanced-MRI of the brain The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality PROCEDURE: Gadolinium Measurements Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Linear GBCAs

Adult participants, who were scheduled for repeated enhanced magnetic resonance imaging (MRI), receive a linear gadoliniumbased contrast agent (GBCA, i.e. Eovist/ Primovist, MultiHance or Omniscan) prior to MRI. Each participant will receive the same GBCA

PROCEDURE: Motor Tests

To assess motor function annually

PROCEDURE: Cognitive Tests

To assess cognitive function annually

PROCEDURE: Unenhanced-MRI of the brain

The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality

PROCEDURE: Gadolinium Measurements

Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration

DRUG: Gadoxetate disodium

Administered as defined by the treating physician as part of routine clinical practice

DRUG: Gadobenate dimeglumine

Administered as defined by the treating physician as part of routine clinical practice

DRUG: Gadodiamide

Administered as defined by the treating physician as part of routine clinical practice

EXPERIMENTAL: Macrocyclic GBCAs

Adult participants, who were scheduled for repeated enhanced magnetic resonance imaging (MRI), receive a macrocyclic gadolinium-based contrast agent (GBCA, i.e. Gadavist/ Gadovist, Dotarem, Magnescope or ProHance) prior to MRI. Each participant will recei

PROCEDURE: Motor Tests

To assess motor function annually

PROCEDURE: Cognitive Tests

To assess cognitive function annually

PROCEDURE: Unenhanced-MRI of the brain

The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality

PROCEDURE: Gadolinium Measurements

Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration

DRUG: Gadoterate meglumine

Administered as defined by the treating physician as part of routine clinical practice

DRUG: Gadobutrol

Administered as defined by the treating physician as part of routine clinical practice

DRUG: Gadoteridol

Administered as defined by the treating physician as part of routine clinical practice

OTHER: No GBCA (Control arm)

Adult participants who were never exposed to any gadolinium-based contrast agent and matching the population characteristics of the two GBCA arms. They will not receive any gadolinium-based contrast agent over the study course, but may undergo clinically

PROCEDURE: Motor Tests

To assess motor function annually

PROCEDURE: Cognitive Tests

To assess cognitive function annually

PROCEDURE: Unenhanced-MRI of the brain

The UE-MRI of the brain will be performed at baseline and at the year 5 visit in order to exclude presence of a significant MRI abnormality

PROCEDURE: Gadolinium Measurements

Blood samples and spontaneous urine specimens will be collected through the course of the study to measure Gd concentration

Primary Outcome Measures	Measure Description	Time Frame
Change of motor function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group	The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests	At baseline, year 5
Change in cognitive function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group	The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests	At baseline, year 5

Secondary Outcome Measures	Measure Description	Time Frame
Change from baseline in the composite endpoints (motor and cognitive) at each of the post-baseline time points (Years 1 to 4) in GBCA-exposed participants as compared to controls.	The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests	At baseline, years 1, 2, 3, 4
Change from baseline for each of the individual tests (motor and cognitive) at each of the post-baseline time points (Years 1 to 5) in GBCA-exposed participants as compared to controls.	The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests	At baseline, years 1, 2, 3, 4
Number of participants with adverse events		At baseline, years 1, 2, 3, 4, 5
Total Gd concentrations (as measured in a central laboratory) in blood and urine samples taken from exposed and control participants at the time of the annual visit		At baseline, years 1, 2, 3, 4, 5

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Nathalie LE FUR, PhD

Phone Number: +33649351166

Email: nathalie.lefur@guerbet.com

Study Contact Backup

Name: Frantz HEBERT

Phone Number: +33680249334

Email: frantz.hebert@guerbet.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Participant must be neurologically normal, defined as free of unstable neurologic and psychiatric disease as confirmed by a normal neurologic examination at screening
Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance imaging (UE-MRI) of the brain at enrollment and at the end of the observation period (5 years)
Participants should have at least 1 of the following indications: a) Medium to high risk for breast cancer or dense breasts undergoing breast cancer screening with MRI, b) Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance for prostate cancer, c) Chronic liver disease (eg, liver cirrhosis limited to Child class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for surveillance of hepatocellular carcinoma development, d) Low-grade colorectal cancer or neuroendocrine tumor undergoing screening for liver metastases or e) Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm) undergoing imaging surveillance.

Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the same GBCA at least annually throughout the 5-year study duration
Prospective participants with up to 3 well documented GBCA administrations prior to study screening are acceptable, provided that the imaging was performed with the same GBCA as the one to be prospectively used in the study. If the GBCA used cannot be identified, he/she cannot be enrolled.

Participants who never had and are not likely to receive any GBCA injection during the course of the study
Each control participant must be willing to undergo UE-MRI of the brain at baseline and at Year 5. In Years 1 to 4, the control participants will undergo their clinically indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures

As evidenced by history or determined in the neurologic exam at screening, concurrent neurological and/or psychiatric disease (or treatments) that could influence the results of the study's motor and cognitive tests (e.g. Cerebrovascular disease, Multiple sclerosis, Neurodegenerative disease, Malignant disease other than listed in indications, Carcinoid tumors, Epilepsy, Prior neurosurgery, Psychotic disorders or any prior psychotic episode not otherwise specified - any documented prior history of chronic schizophrenia, Remittent or current medically confirmed major depressive disorder or bipolar disorder, History of long-term major depression or bipolar affective disorder with an active episode in the past 2 to 5 years, Neurodevelopmental disorders (eg, trisomy 21), Uncontrolled severe migraine, Uncontrolled or controlled anxiety or depression within 6 months before enrollment, Screening scores of ≤24 on the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS)).
Prior, planned, or ongoing chemotherapy or brain irradiation
Use of concomitant medication(s) affecting neuro-cognitive or motor function
Substance or alcohol abuse as determined by the investigator
Alcoholic cirrhosis
Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
History of environmental/occupational/other exposure to one or more chemicals that may affect cognitive and/or motor function, including, but not limited to, heavy metals (arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides, solvents, or carbon monoxide.
Clinical indications requiring >1 contrast enhanced magnetic resonance imaging (CE-MRI) every 6 months
Pregnant or nursing (lactating) women
Presence of any metal-containing joint implants/prostheses

Participants with any previous exposure to a GBCA.
Participants with any contraindication to UE-MRI examinations.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Bayer AG (Sponsor)
Bracco (Sponsor)
GEHC (Sponsor)

Investigators

Publications

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