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

Cognitive Function Clinical Trial

— ODYSSEY  

Official title:

Prospective Evaluation of Potential Effects of Repeated Gadolinium-based Contrast Agent (GBCA) Administrations of the Same GBCA on Motor and Cognitive Functions in Neurologically Normal Adults in Comparison to a Non-GBCA Exposed Control Group

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04373564
• Other study ID #: DGD-44-065
• Secondary ID: 20405GMRA-105GE-
• Status: Recruiting
• Phase: Phase 4
• Start date: March 24, 2021
• Est. completion date: December 31, 2028

Study information

• Verified date: January 2023
• Source: Guerbet
• Contact: Nathalie LE FUR, PhD
• Phone: +33649351166
• Email: nathalie.lefur[@]guerbet.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2076
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

• 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.

In addition, for participants in the GBCA Arms only:

• 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.

For the Control Arm:

• 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

Exclusion Criteria:

• 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

In addition, for participants in either of the GBCA Arms only:

• Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be administered during the course of the study.

For participants in the Control Arm only:

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

Related Conditions & MeSH terms

• Cognitive Function
• Contrast Media
• Motor Function

Intervention

Procedure:
• Motor Tests
To assess motor function annually
• Cognitive Tests
To assess cognitive function annually
• 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
• 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
• Gadobenate dimeglumine
Administered as defined by the treating physician as part of routine clinical practice
• Gadodiamide
Administered as defined by the treating physician as part of routine clinical practice
• Gadoterate meglumine
Administered as defined by the treating physician as part of routine clinical practice
• Gadobutrol
Administered as defined by the treating physician as part of routine clinical practice
• Gadoteridol
Administered as defined by the treating physician as part of routine clinical practice

Locations

Country	Name	City	State
Brazil	Instituto Baía Sul de Ensino e Pesquisa (IEP)	Florianopolis	Santa Catarina
Brazil	Liga Norte-Rio-Grandense Contra o Câncer	Natal	Rio Grande Do Norte
Brazil	Instituto Mederi de Pesquisa e Saude	Passo Fundo	RS
Brazil	Hospital Moinhos de Vento	Porto Alegre	RS
Brazil	CEMEC - Oncológica	Sao Bernardo Do Campo
Brazil	CEMEC - Oncológica	São Bernardo do Campo	Sao Paulo
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José Do Rio Preto	SP
Brazil	CPCLIN - Centro de Pesquisas Clínicas Ltda.	São Paulo	SP
Brazil	Hospital Santa Marta	Taguatinga	Distrito Federal
Canada	G. Kenneth Jansz Medical Professional Corporation	Burlington	Ontario
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Italy	Azienda Ospedaliera Universitaria di Trieste	Trieste
Korea, Republic of	Inje University Busan Paik Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Hallym University Chuncheon Sacred Heart Hospital	Chuncheon	Gangwon-do
Korea, Republic of	Chonnam National University Hospital	Gwangju	Gyeonggi-do
Korea, Republic of	Chosun University Hospital	Gwangju
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Gangnam Severance Hospital, Yonsei University Health System	Seoul
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Russian Federation	FSBI "National medical scientific center of psychiatry and neurology n.a. V.M. Bekhterev" Adolescent	Saint-Petersburg
Russian Federation	FSBI North-West Federal Medical Research Center n.a. V.A. Almazov of MoH RF	Saint-Petersburg
Russian Federation	LLC Medical Center Mart	Saint-Petersburg
Russian Federation	RSBIH "Smolensk Regional Clinical Hospital"	Smolensk
Russian Federation	Federal State Budgetary Scientific Institution "Tomsk National Research Medical Centre of the Russia	Tomsk
Russian Federation	SBIH Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan	Ufa
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston University Medical Center	Boston	Massachusetts
United States	Massachussets General Hospital	Boston	Massachusetts
United States	UNC School of Medicine	Chapel Hill	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Penn State Hershey Medical Center	Hershey	Pennsylvania
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Wisconsin	Madison	Wisconsin
United States	ActivMed Practices & Research, Inc.	Methuen	Massachusetts
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Albert Einstein Healthcare Network	Philadelphia	Pennsylvania
United States	Department of Radiology	Saint Louis	Missouri
United States	Scottsdale Medical Imaging, LLC	Scottsdale	Arizona
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Guerbet	Bayer AG (Sponsor), Bracco (Sponsor), GEHC (Sponsor)

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Italy,  Korea, Republic of,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	Number of participants with adverse events		At baseline, years 1, 2, 3, 4, 5
Secondary	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