Evaluation of Long-term Effects of Repeated Gadolinium-based Contrast Agents on Motor and Cognitive Functions in Neurologically Normal Adults

The primary objective of this study is to prospectively assess the potential effect of repeated exposure to either a linear or a macrocyclic **gadolinium-based contrast agent** (GBCA) on changes in motor and cognitive function from baseline to Year 5 among neurologically normal adults. This is compared to a matched non-GBCA-exposed control group. The clinical relevance of this objective lies in understanding the long-term impact of GBCAs, which are commonly used in magnetic resonance imaging (MRI), on neurological functions in individuals without pre-existing neurological conditions.

Secondary objectives include: - Assessing the change from baseline in composite endpoints (motor and cognitive) at each post-baseline time point (Years 1 to 4) in GBCA-exposed participants compared to controls. - Evaluating the change from baseline for each individual test (motor and cognitive) at each post-baseline time point (Years 1 to 5) in GBCA-exposed participants compared to controls. - Evaluating safety through the collection of adverse events. - Assessing total gadolinium concentrations in blood and urine samples from exposed and control participants at the time of the annual visit.

The clinical trial involves a total of **964 participants** who are neurologically normal adults, aged between the legal majority age and 65 years. The study population includes both **male and female** subjects, and it is noted that a vulnerable population is selected. Participants were chosen based on their neurological health status, confirmed by a normal neurologic examination at screening, and their willingness to undergo unenhanced magnetic resonance imaging (UE-MRI) of the brain at enrollment and at the end of the observation period, which spans 5 years. The trial includes individuals with specific medical indications such as medium to high risk for breast cancer, elevated prostate-specific antigen (PSA) under active surveillance for prostate cancer, chronic liver disease for hepatocellular carcinoma surveillance, low-grade colorectal cancer or neuroendocrine tumor under surveillance for liver metastases, and branch-duct intraductal papillary mucinous neoplasm of the pancreas. Participants in the GBCA arms are expected to undergo at least five GBCA-enhanced MR examinations annually throughout the study duration. The control group consists of participants who have never had and are not likely to receive any GBCA injection during the study. The selection process ensures that participants are matched with the population characteristics of the GBCA study arms, including clinical indication for imaging, geographic region, and age group, with additional factors such as education level and sex being recorded for statistical analysis.

The clinical trial is designed to evaluate the potential effects of repeated administrations of **gadolinium-based contrast agents (GBCAs)** on motor and cognitive functions in neurologically normal adults. This is a Phase IV, randomized, double-blind, controlled study comparing two groups: those exposed to GBCAs and a matched non-GBCA-exposed control group. The trial is set to span over a period of five years, with the estimated recruitment start date being May 5, 2023, and the estimated end date being January 17, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, neurological status, and imaging indications. The primary inclusion criteria require participants to be adults under 65 years old, neurologically normal, and willing to undergo unenhanced magnetic resonance imaging (UE-MRI) at enrollment and at the end of the study. Participants in the GBCA arms must have at least five GBCA-enhanced MR examinations annually, while control participants must not have any GBCA exposure during the study.

Following the screening visit, participants will attend annual follow-up visits where changes in motor and cognitive functions will be assessed using composite z scores. These visits will also involve the collection of blood and urine samples to measure total gadolinium concentrations, and the recording of any adverse events (AEs) that occur post-consent. The end-of-study visit will occur at Year 5, where final assessments will be conducted to evaluate the primary endpoints, which include changes in motor and cognitive functions from baseline.

The expected length of participant involvement is five years, with conditions for early termination including the inability to comply with study procedures or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the long-term impact of repeated GBCA exposure, contributing valuable insights into the safety and efficacy of these agents in clinical practice.

The clinical trial involves the administration of several **gadolinium-based contrast agents (GBCAs)**, each serving as a magnetic resonance contrast agent. **Gadoxetic acid, disodium** is utilized in this study as a solution for injection. It is administered intravenously at a dosage of 0.1 milliliters per kilogram, with a maximum daily and total dose of 0.1 milliliters per kilogram. The treatment period is limited to a single day. This agent is not formulated for pediatric use and is chemically derived.

**Gadoteridol** is another GBCA used in the trial, available as a solution for injection in a pre-filled syringe. It is administered intravenously at a dosage of 0.3 millimoles per kilogram, with a maximum daily and total dose of 0.3 millimoles per kilogram. The treatment period is also restricted to one day. This agent is not specifically formulated for pediatric patients.

**Gadobenate dimeglumine** is included in the study as a solution for injection, also available in a pre-filled syringe. It is administered intravenously at a dosage of 0.05 millimoles per kilogram, with a maximum daily and total dose of 0.05 millimoles per kilogram. The treatment period is limited to one day, and it is not a pediatric formulation.

**Gadoteric acid** is administered as a solution for injection, with an intravenous route. The dosage is set at 0.1 millimoles per kilogram, with a maximum daily and total dose of 0.1 millimoles per kilogram. The treatment period is confined to a single day, and it is not formulated for pediatric use.

**Gadobutrol** is another GBCA used in the trial, provided as a solution for injection. It is administered intravenously at a dosage of 1.5 millimoles per kilogram, with a maximum daily and total dose of 1.5 millimoles per kilogram. The treatment period is restricted to one day, and it is not specifically formulated for pediatric patients.

All agents are administered intravenously and are not formulated for pediatric use. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance is monitored through adherence to the dosing schedule and administration route. The trial aims to evaluate the potential effects of repeated GBCA administrations on motor and cognitive functions in neurologically normal adults.

The efficacy of the clinical trial will be assessed through the evaluation of changes in motor and cognitive functions over a five-year period. The co-primary endpoints are defined as the change from baseline to Year 5 in motor function and cognitive function, expressed by the composite z score. This score is calculated as the weighted sum of the z scores of individual tests, with each test assigned equal weight due to their equal importance. Secondary endpoints include changes from baseline in the composite endpoint during Years 1 to 4 and in each individual test of motor and cognitive function from Years 1 to 5.

Additional assessments will include the evaluation of adverse events (AEs), which will be recorded at baseline and each annual visit. This will involve documenting signs and symptoms, onset date and time, severity, causality, seriousness, treatment, and outcome. Furthermore, total **gadolinium** concentrations in blood plasma and urine samples will be measured at baseline and each annual visit. If contrast-enhanced magnetic resonance imaging (CE-MRI) is performed at the same visit, blood and urine samples will be collected prior to imaging.