Clinical trial NCT04373564: Effect on Body Movement and Mental Skills in Patients Who Received Gadolinium-based Contrast Media for Magnetic Resonance Examination Multiple Times Within 5 Years
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Motor Function
Cognitive Function
Contrast Media
Keywords: 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
Lead sponsor: Guerbet
Sponsor class: INDUSTRY
Collaborators: name: Bayer AG (Sponsor)
name: Bracco (Sponsor)
name: GEHC (Sponsor)
First posted: 2020-05-04
Enrollment: 2076
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change of motor function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group
timeFrame: At baseline, year 5
measure: Change in cognitive function from baseline to year 5 in comparison to a matched non-GBCA-exposed control group
timeFrame: At baseline, year 5
Secondary outcomes:
measure: 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.
timeFrame: At baseline, years 1, 2, 3, 4
measure: 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.
timeFrame: At baseline, years 1, 2, 3, 4
measure: Number of participants with adverse events
timeFrame: At baseline, years 1, 2, 3, 4, 5
measure: 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
timeFrame: At baseline, years 1, 2, 3, 4, 5
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Scottsdale Medical Imaging, LLC
state: Arizona
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Boston
country: United States
facility: Massachussets General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Methuen
country: United States
facility: ActivMed Practices & Research, Inc.
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Department of Radiology
state: Missouri
city: Chapel Hill
country: United States
facility: UNC School of Medicine
state: North Carolina
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Healthcare Network
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Taguatinga
country: Brazil
facility: Hospital Santa Marta
state: Distrito Federal
city: Natal
country: Brazil
facility: Liga Norte-Rio-Grandense Contra o Câncer
state: Rio Grande Do Norte
city: Passo Fundo
country: Brazil
facility: Instituto Mederi de Pesquisa e Saude
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: RS
city: Florianopolis
country: Brazil
facility: Instituto Baía Sul de Ensino e Pesquisa (IEP)
state: Santa Catarina
city: São Bernardo do Campo
country: Brazil
facility: CEMEC - Oncológica
state: Sao Paulo
city: São José Do Rio Preto
country: Brazil
facility: Fundação Faculdade Regional de Medicina de São José do Rio Preto
state: SP
city: São Paulo
country: Brazil
facility: CPCLIN - Centro de Pesquisas Clínicas Ltda.
state: SP
city: São Paulo
country: Brazil
facility: Albert Einstein Sociedade Beneficente Israelita Brasileira
state: SP
city: Sao Bernardo Do Campo
country: Brazil
facility: CEMEC - Oncológica
city: Burlington
country: Canada
facility: G. Kenneth Jansz Medical Professional Corporation
state: Ontario
city: Paris
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
city: Strasbourg
country: France
facility: CHU Strasbourg - Hôpital Hautepierre
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
state: Baden Wuerttemberg
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
city: Trieste
country: Italy
facility: Azienda Ospedaliera Universitaria di Trieste
city: Chuncheon
country: Korea, Republic of
facility: Hallym University Chuncheon Sacred Heart Hospital
state: Gangwon-do
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
state: Gyeonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Gwangju
country: Korea, Republic of
facility: Chosun University Hospital
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Omsk
country: Russian Federation
facility: BHI of Omsk region "Clinical Oncology Dispensary"
city: Saint-Petersburg
country: Russian Federation
facility: FSBI "National medical scientific center of psychiatry and neurology n.a. V.M. Bekhterev" Adolescent
city: Saint-Petersburg
country: Russian Federation
facility: FSBI North-West Federal Medical Research Center n.a. V.A. Almazov of MoH RF
city: Saint-Petersburg
country: Russian Federation
facility: LLC Medical Center Mart
city: Smolensk
country: Russian Federation
facility: RSBIH "Smolensk Regional Clinical Hospital"
city: Tomsk
country: Russian Federation
facility: Federal State Budgetary Scientific Institution "Tomsk National Research Medical Centre of the Russia
city: Ufa
country: Russian Federation
facility: SBIH Republican Clinical Oncological Dispensary of the MoH of Republic Bashkortostan
Study officials:
References: