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

• Sponsor: Guerbet (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04373564
• Collaborator: Bayer AG (Sponsor) (Other), Bracco (Sponsor) (Other), GEHC (Sponsor) (Other)
• Enrollment: 2,076
• Locations: 32
• Arms: 3
• Anticipated Duration (Months): 93.3
• Patients Per Site: 64.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
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	Phase 4

Detailed 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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 2076 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: Mar 24, 2021
• Anticipated Primary Completion Date: Dec 31, 2028
• Anticipated Study Completion Date: Dec 31, 2028

Arms and Interventions

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 throughout the study.	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; Other Names: Eovist Primovist BAY86-4873 ; Drug: Gadobenate dimeglumine; Administered as defined by the treating physician as part of routine clinical practice; Other Names: MultiHance ; Drug: Gadodiamide; Administered as defined by the treating physician as part of routine clinical practice; Other Names: Omniscan
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 receive the same GBCA throughout the study.	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; Other Names: Dotarem Magnescope ; Drug: Gadobutrol; Administered as defined by the treating physician as part of routine clinical practice; Other Names: BAY86-4875 Gadavist Gadovist ; Drug: Gadoteridol; Administered as defined by the treating physician as part of routine clinical practice; Other Names: ProHance
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 indicated imaging (e.g. unenhanced magnetic resonance imaging (MRI), unenhanced or enhanced computed tomography, ultrasound and/or X-ray).	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

Outcome Measures

Primary Outcome Measures

1. Change of motor function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group [At baseline, year 5]

   The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests

2. Change in cognitive function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group [At baseline, year 5]

   The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests

Secondary Outcome Measures

1. 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. [At baseline, years 1, 2, 3, 4]

   The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests

2. 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. [At baseline, years 1, 2, 3, 4]

   The endpoint is a composite z score, defined as the weighted sum of the z scores of the individual tests

3. Number of participants with adverse events [At baseline, years 1, 2, 3, 4, 5]

4. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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,

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scottsdale Medical Imaging, LLC	Scottsdale	Arizona	United States	85260
2	Yale University School of Medicine	New Haven	Connecticut	United States	06520
3	University of Chicago Medical Center	Chicago	Illinois	United States	60637
4	Central Illinois Radiological Associate, Ltd.	Peoria	Illinois	United States	61637
5	Massachussets General Hospital	Boston	Massachusetts	United States	02114
6	Boston University Medical Center	Boston	Massachusetts	United States	02118
7	ActivMed Practices & Research, Inc.	Methuen	Massachusetts	United States	01844
8	Department of Radiology	Saint Louis	Missouri	United States	63110
9	UNC School of Medicine	Chapel Hill	North Carolina	United States	27599
10	UT Southwestern Medical Center	Dallas	Texas	United States	75390
11	MD Anderson Cancer Center	Houston	Texas	United States	77030
12	University of Wisconsin	Madison	Wisconsin	United States	53792
13	Liga Norte-Rio-Grandense Contra o Câncer	Natal	Rio Grande Do Norte	Brazil	59075-740
14	Instituto Mederi de Pesquisa e Saude	Passo Fundo	RS	Brazil	99010-120
15	Hospital Moinhos de Vento	Porto Alegre	RS	Brazil	90035-001
16	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José Do Rio Preto	SP	Brazil	15090-000
17	CPCLIN - Centro de Pesquisas Clínicas Ltda.	São Paulo	SP	Brazil	01228-200
18	CEMEC - Oncológica	Sao Bernardo Do Campo		Brazil
19	Hallym University Chuncheon Sacred Heart Hospital	Chuncheon	Gangwon-do	Korea, Republic of	24253
20	Chonnam National University Hospital	Gwangju	Gyeonggi-do	Korea, Republic of	61469
21	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
22	Inje University Busan Paik Hospital	Busan		Korea, Republic of	47392
23	Pusan National University Hospital	Busan		Korea, Republic of	49241
24	Chosun University Hospital	Gwangju		Korea, Republic of	61453
25	Gangnam Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	06273
26	Chung-Ang University Hospital	Seoul		Korea, Republic of	06973
27	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk		Russian Federation	644013
28	FSBI "National medical scientific center of psychiatry and neurology n.a. V.M. Bekhterev" Adolescent	Saint-Petersburg		Russian Federation	192019
29	FSBI North-West Federal Medical Research Center n.a. V.A. Almazov of MoH RF	Saint-Petersburg		Russian Federation	197341
30	LLC Medical Center Mart	Saint-Petersburg		Russian Federation	199178
31	Federal State Budgetary Scientific Institution "Tomsk National Research Medical Centre of the Russia	Tomsk		Russian Federation	634009
32	SBIH Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan	Ufa		Russian Federation	450054

Sponsors and Collaborators

• Guerbet
• Bayer AG (Sponsor)
• Bracco (Sponsor)
• GEHC (Sponsor)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Guerbet
• ClinicalTrials.gov Identifier: NCT04373564
• Other Study ID Numbers: DGD-44-065; 20405; GMRA-105; GE-041-081; IQVIA-ODYS-001-LZA45541
• First Posted: May 4, 2020
• Last Update Posted: Feb 23, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Guerbet: Motor function assessment; Cognitive function assessment; Magnetic Resonance Imaging (MRI); Gadolinium; Gadolinium-based contrast agent (GBCA); Gadolinium retention; Breast cancer; Prostate cancer; Hepatocellular carcinoma; Colorectal cancer; Neuroendocrine tumor; Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas
• Additional relevant MeSH terms: Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate

Study Results

No Results Posted as of Feb 23, 2022