Gadolinium-Based Contrast Media Effects on Motor and Cognitive Functioning

(ODYSSEY Trial)

Recruiting at 34 trial locations

Overseen By Frantz HEBERT

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Guerbet

Must not be taking: Neuro-cognitive drugs

Disqualifiers: Neurological, Psychiatric, Renal, Alcoholic cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

2076 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that participants do not use medications affecting neuro-cognitive or motor function. If you are taking such medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Gadobenate dimeglumine and similar gadolinium-based contrast agents on motor and cognitive functioning?

The study comparing gadodiamide injection and gadopentetate dimeglumine found that gadodiamide was a safe and effective contrast agent for imaging the central nervous system, with contrast enhancement observed in a significant number of patients with structural abnormalities. This suggests that gadolinium-based contrast agents can effectively enhance imaging, which may indirectly support their use in assessing conditions affecting motor and cognitive functions. ^{1 2 3 4 5}

Is gadolinium-based contrast media safe for humans?

Gadolinium-based contrast agents, like gadodiamide and gadobenate dimeglumine, have been studied for safety in humans. Some people experienced mild and temporary side effects, but these were not serious and did not require treatment. Overall, these agents are considered safe for use in medical imaging. ^{1 2 6 7 8}

How does the drug used in the Gadolinium-Based Contrast Media Effects on Motor and Cognitive Functioning trial differ from other treatments?

The trial focuses on the effects of gadolinium-based contrast media, which is unique because it is typically used in imaging tests like MRIs to enhance the visibility of internal structures, rather than as a direct treatment for cognitive or motor function. This contrasts with other treatments like galantamine or piribedil, which are specifically used to improve cognitive function or memory. ^{9 10 11 12 13}

Eligibility Criteria

Adults up to 65 years old needing regular MRI scans for conditions like medium/high-risk breast cancer, prostate cancer surveillance, or chronic liver disease. Participants must be neurologically stable with no severe kidney issues, not pregnant/nursing, and free from heavy metal exposure that could affect brain function.

Inclusion Criteria

I am participating in the GBCA Arms of the study.

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.

I agree to have specific brain scans now and in 5 years, with other scans as needed in between.

Exclusion Criteria

I am participating in a trial that involves Gadolinium-Based Contrast Agents.

My kidney function is reduced with an eGFR below 60.

I need more than one MRI with contrast every 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Initial assessment of motor and cognitive functions and collection of baseline data

1 visit

1 visit (in-person)

Annual Imaging and Assessment

Participants undergo annual MRI or other imaging tests and assessments of motor and cognitive functions

5 years

7 visits (in-person) over 5 years

Follow-up

Participants are monitored for changes in motor and cognitive functions after the study period

1 year

Treatment Details

Interventions

• Gadobenate dimeglumine
• Gadobutrol
• Gadodiamide
• Gadoterate meglumine
• Gadoteridol
• Gadoxetate disodium

Trial Overview The study is examining if repeated use of gadolinium-based contrast agents (GBCAs) during MRIs over five years affects motor skills and cognitive functions. It involves annual MRIs and tests on body movement/mental skills across four GBCA types versus unenhanced-MRI controls.

Participant Groups

Group I: No GBCA (Control arm) Experimental Treatment 4 Interventions

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).

Group II: Macrocyclic GBCAs Experimental Treatment 7 Interventions

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.

Group III: Linear GBCAs Experimental Treatment 7 Interventions

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.

Who Is Running the Clinical Trial?

Guerbet

Lead Sponsor

Trials

72

Recruited

94,600+

David Hale

Guerbet

Chief Executive Officer since 2020

MBA from IMD

Philippe Bourrinet

Guerbet

Chief Medical Officer since 2023

MD

Bayer AG (Sponsor)

Collaborator

Trials

1

Recruited

2,100+

Bracco (Sponsor)

Collaborator

Trials

1

Recruited

2,100+

GEHC (Sponsor)

Collaborator

Trials

1

Recruited

2,100+

Findings from Research

In a study of 194,400 intravenous administrations of gadolinium-based contrast agents (GBCA), the overall rate of adverse reactions was low at 0.1%, with most reactions being mild.

Among the different GBCA types, gadofosveset trisodium had the highest reaction rate at 0.80%, while gadopentetate dimeglumine had the lowest at 0.09%, indicating variability in safety profiles among these agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse allergic reactions to linear ionic gadolinium-based contrast agents: experience with 194, 400 injections. Aran, S., Shaqdan, KW., Abujudeh, HH.[2015]

In a study involving 60 adult patients, gadodiamide injection was found to be a safe contrast agent, with only 10 adverse events reported, most of which were transient and required no treatment.

Both gadodiamide and gadopentetate dimeglumine showed similar diagnostic utility, with contrast enhancement observed in 60% of patients using gadodiamide and 44% using gadopentetate, indicating no significant difference in overall efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gadodiamide injection and gadopentetate dimeglumine. A double-blind study in MR imaging of the CNS. Myhr, G., Rinck, PA., Børseth, A.[2015]

Patients who received gadobenate dimeglumine after prior exposure to gadodiamide showed a significant increase in T1 signal intensity in the dentate nucleus compared to those without previous gadodiamide exposure, indicating potential gadolinium deposition effects.

The study suggests that prior administration of less stable gadolinium-based contrast agents (like gadodiamide) may enhance the effects of subsequent administrations of more stable agents (like gadobenate dimeglumine), although the exact mechanism and implications for safety require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide. Ramalho, J., Semelka, RC., AlObaidy, M., et al.[2020]

In a study of 32 patients with posttreatment glioma, gadobutrol (one-molar) and gadoterate meglumine (half-molar) showed no significant differences in key dynamic contrast-enhanced imaging parameters, indicating they can be used interchangeably.

However, gadobutrol demonstrated a significantly higher wash-in rate and a lower washout rate compared to gadoterate meglumine, suggesting slight differences in how these agents behave during imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Dynamic Contrast-Enhancement Parameters between Gadobutrol and Gadoterate Meglumine in Posttreatment Glioma: A Prospective Intraindividual Study. Park, JE., Kim, JY., Kim, HS., et al.[2021]

In a study of 211 patients comparing gadoxetic acid and gadoteric acid for liver MRI, gadoxetic acid resulted in significantly poorer image quality during the triple arterial phases, despite better pre-contrast images.

The overall image quality improved from the first to the third arterial phases for both contrast agents, suggesting that the third arterial phase images are the most reliable for diagnostic purposes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of gadoxetic acid on image quality of arterial multiphase magnetic resonance imaging of liver: comparison study with gadoteric acid-enhanced MRI. Sim, KC., Park, BJ., Han, NY., et al.[2020]

A total of 424 risk signals related to adverse events (AEs) were identified from the FAERS database for four gadolinium-based contrast agents (GBCAs) over an 18-year period, highlighting significant safety concerns associated with these agents.

The study revealed that some adverse events linked to GBCAs were not included in their package inserts, indicating a need for further research to ensure patient safety and awareness of potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Data mining and analysis of the adverse events derived signals of 4 gadolinium-based contrast agents based on the US Food and drug administration adverse event reporting system. Wang, L., Wang, Y., Zhao, Q.[2023]

In a study of 10,595 patients undergoing MRI with gadolinium-based contrast agents, the overall incidence of acute adverse reactions was low at 0.45%, with no severe reactions reported.

Younger patients were found to be at a higher risk for experiencing acute adverse reactions, and gadoxetate disodium had a higher incidence of reactions (0.82%) compared to gadopentetate dimeglumine (0.43%), indicating that while all agents are generally safe, some may carry slightly more risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and severity of acute adverse reactions to four different gadolinium-based MR contrast agents. Okigawa, T., Utsunomiya, D., Tajiri, S., et al.[2019]

In a study involving 3092 subjects across 79 clinical trials, gadobenate dimeglumine (MultiHance) was found to have a safety profile comparable to placebo and other contrast agents, with only 14% of adult subjects reporting adverse events.

MultiHance was well tolerated in special populations, including children and individuals with liver or kidney impairment, showing no significant increase in adverse events or negative effects on cardiac function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of gadobenate dimeglumine (MultiHance): Summary of findings from clinical studies and postmarketing surveillance. Shellock, FG., Parker, JR., Venetianer, C., et al.[2022]

In a study involving 15 mild traumatic brain injury (mTBI) patients and 17 healthy controls, the mixed D1/D2 agonist pergolide improved working memory performance in mTBI patients compared to the selective D2 agonist bromocriptine.

Functional MRI results indicated that pergolide increased activation in brain regions associated with working memory, particularly in the left inferior frontal gyrus, suggesting that targeting D1 receptors may be a promising strategy for treating cognitive deficits after mTBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Effects of Pergolide and Bromocriptine on Working Memory Performance and Brain Activation after Mild Traumatic Brain Injury. Flashman, LA., McDonald, BC., Ford, JC., et al.[2022]

Piribedil, at a dose of 10 mg/kg, significantly improved memory performance in aged mice, particularly in tasks assessing relational and declarative memory, while bromocriptine showed no such effects.

Both dopamine agonists enhanced memory in young adult rats, but only piribedil demonstrated lasting benefits against age-related memory impairments, suggesting its potential as a treatment for cognitive deficits in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effects of the dopaminergic agonists piribedil and bromocriptine in three different memory paradigms in rodents. Marighetto, A., Valerio, S., Philippin, JN., et al.[2013]

In a study involving 2,048 subjects with mild cognitive impairment, galantamine did not significantly reduce the rate of conversion to dementia compared to placebo over 24 months.

Galantamine was generally well tolerated, with nausea being the most common side effect, affecting 29% of participants, while the overall mortality rate was slightly higher in the galantamine group (1.4%) compared to placebo (0.3%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of galantamine in subjects with mild cognitive impairment. Winblad, B., Gauthier, S., Scinto, L., et al.[2022]

Antiepileptic drugs (AEDs) like topiramate, lamotrigine, and others can cause cognitive dysfunction, but the exact mechanisms behind these effects are not well understood.

Recent studies using functional MRI (fMRI) have begun to reveal how different AEDs affect brain activity during cognitive tasks, highlighting specific drug-related changes in brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of antiepileptic drugs on cognitive functional magnetic resonance imaging. Beltramini, GC., Cendes, F., Yasuda, CL.[2022]

In a study of 515 elderly patients, piribedil, a dopamine agonist, significantly improved memory impairment, vertigo, and tinnitus, with 20% experiencing complete resolution and 72.6% showing improvement after one month of treatment.

The treatment was well tolerated, with a low incidence of side effects and high compliance among patients, indicating its acceptability as a therapeutic option for age-related dopamine decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of memory impairment, vertigo and tinnitus in the elderly with piribedil in an Indian general practice setting. Hastak, SM.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Adverse allergic reactions to linear ionic gadolinium-based contrast agents: experience with 194, 400 injections. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Gadodiamide injection and gadopentetate dimeglumine. A double-blind study in MR imaging of the CNS. [2015]

3. Germany pubmed.ncbi.nlm.nih.gov

Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Comparison of Dynamic Contrast-Enhancement Parameters between Gadobutrol and Gadoterate Meglumine in Posttreatment Glioma: A Prospective Intraindividual Study. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Effects of gadoxetic acid on image quality of arterial multiphase magnetic resonance imaging of liver: comparison study with gadoteric acid-enhanced MRI. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Data mining and analysis of the adverse events derived signals of 4 gadolinium-based contrast agents based on the US Food and drug administration adverse event reporting system. [2023]

7. Japan pubmed.ncbi.nlm.nih.gov

Incidence and severity of acute adverse reactions to four different gadolinium-based MR contrast agents. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Safety of gadobenate dimeglumine (MultiHance): Summary of findings from clinical studies and postmarketing surveillance. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Differential Effects of Pergolide and Bromocriptine on Working Memory Performance and Brain Activation after Mild Traumatic Brain Injury. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Comparative effects of the dopaminergic agonists piribedil and bromocriptine in three different memory paradigms in rodents. [2013]

11. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of galantamine in subjects with mild cognitive impairment. [2022]

12. China pubmed.ncbi.nlm.nih.gov

The effects of antiepileptic drugs on cognitive functional magnetic resonance imaging. [2022]

13. India pubmed.ncbi.nlm.nih.gov

Treatment of memory impairment, vertigo and tinnitus in the elderly with piribedil in an Indian general practice setting. [2013]