(21181) A multicenter, randomized, prospective double-blind, cross over Phase 3 study to evaluate the efficacy and safety of 0.04 mmol Gd/kg body weight of gadoquatrane for MRI in adults with known or suspected pathology of the central nervous system (CNS), compared to 0.1 mmol Gd/kg approved macrocyclic gadolinium-based contrast agents (GBCAs)

The primary objective of this study is to demonstrate the **non-inferior efficacy** of gadoquatrane compared to macrocyclic gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI) for the assessment of central nervous system pathology. This is clinically relevant as it aims to establish gadoquatrane as a viable alternative to existing contrast agents, potentially offering similar diagnostic capabilities with a lower dose of gadolinium, which may reduce the risk of gadolinium retention in patients.

Secondary objectives include:

• Demonstrating the non-inferior diagnostic performance of gadoquatrane compared to macrocyclic GBCAs.
• Demonstrating superior efficacy of gadoquatrane compared to unenhanced MRI.
• Describing diagnostic performance based on contrast-enhanced MRIs with gadoquatrane compared to macrocyclic GBCAs.
• Describing efficacy based on contrast-enhanced MRIs with gadoquatrane compared to macrocyclic GBCAs.
• Evaluating the number of lesions with gadoquatrane-enhanced MRI compared to unenhanced imaging and to macrocyclic GBCAs.
• Demonstrating a similar overall safety profile of 0.04 mmol Gd/kg gadoquatrane compared to 0.1 mmol Gd/kg of macrocyclic GBCAs.

The clinical trial involves a total of **326 participants** who are being evaluated for **contrast enhancement in magnetic resonance imaging** to assess central nervous system pathology. The study population includes both male and female subjects, aged 18 years and older, who have a clinical indication for a contrast-enhanced MRI. Participants are required to undergo two MRI examinations, one with gadoquatrane and one with a comparator macrocyclic GBCA. The trial includes individuals who are capable of undergoing study-related procedures and are not pregnant or breastfeeding, with female participants adhering to local contraceptive regulations. The selection process ensures that participants have a known or suspected CNS pathology and are suitable for the procedures as per the investigator's judgment. The trial population is diverse, including vulnerable groups, and is representative of those who would typically require such diagnostic imaging in clinical practice.

The clinical trial is a multicenter, randomized, double-blind, crossover Phase 3 study designed to evaluate the efficacy and safety of **gadoquatrane** at a dose of 0.04 mmol Gd/kg body weight for magnetic resonance imaging (MRI) in adults with known or suspected central nervous system (CNS) pathology. The trial compares this with 0.1 mmol Gd/kg of approved macrocyclic gadolinium-based contrast agents (GBCAs). The primary objective is to demonstrate the non-inferior efficacy of gadoquatrane compared to macrocyclic GBCAs. The trial is expected to run from September 2023 to November 2024, with participant involvement lasting approximately two weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), clinical indication for contrast-enhanced MRI, and ability to undergo study-related procedures. Female participants must adhere to local contraceptive regulations. The study involves two contrast-enhanced MRI examinations: one with gadoquatrane and one with a comparator macrocyclic GBCA. These visits are designed to evaluate primary endpoints, including visualization parameters assessed by a blinded independent central review (BICR). Secondary endpoints include sensitivity and specificity for lesion detection and the overall diagnostic clinical value of the MRI scans.

The trial includes follow-up visits to monitor for any treatment-emergent adverse events, with a focus on serious adverse events occurring within 24 ± 4 hours post-injection. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are addressed. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The trial's design ensures rigorous assessment of the investigational product's safety and efficacy, contributing valuable data to the field of CNS imaging.

The clinical trial involves the administration of **gadoquatrane**, marketed under the sponsor product code BAY 1747846, as the experimental medication. This compound is provided in a **solution for injection** form and is administered **intravenously**. The maximum daily dose is 0.04 mmol per kilogram of body weight, with a total maximum dose of 0.08 mmol. The treatment period is limited to a maximum of 2 days. Gadoquatrane is of chemical origin and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the study includes comparator treatments with approved macrocyclic gadolinium-based contrast agents (**GBCAs**), namely **gadoteric acid**, **gadobutrol**, and **gadoteridol**. These agents are also of chemical origin and are administered in a pharmaceutical form identified as PHF00231MIG. Each of these comparator agents is administered **intravenously** with a maximum daily dose of 0.1 mmol per kilogram of body weight and a total maximum dose of 0.2 mmol. The treatment period for these agents is similarly capped at 2 days. These comparator treatments are not pediatric formulations and are used to evaluate the non-inferiority of gadoquatrane in terms of efficacy and safety for MRI in adults with known or suspected central nervous system pathology.

The efficacy of the investigational product, **gadoquatrane**, will be assessed in a multicenter, randomized, prospective double-blind, crossover Phase 3 clinical trial. The primary endpoint for evaluating efficacy involves three visualization parameters: enhancement on a 4-point scale (4PS), delineation on a 4PS, and morphology on a 3-point scale (3PS). These parameters will be assessed through a separate blinded evaluation of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic gadolinium-based contrast agents (GBCAs) by a Blinded Independent Central Review (BICR).

Secondary endpoints include the sensitivity and specificity for the detection of lesions, assessed by BICR, and the overall diagnostic clinical value of the MRI scans. This value is based on the evaluation of diagnostic descriptive imaging features adapted from radiologic reporting standards, such as detection/exclusion of enhancing pathology, location, extent, and pattern of enhancement on a 5-point scale (5PS). Additionally, the confidence in diagnosis will be measured on a 4PS by both BICR and the Investigator. The number of lesions and enhancing lesions seen on the MRI scans will also be recorded. The efficacy assessments will be conducted through a series of MRI examinations, comparing the investigational product with approved macrocyclic GBCAs.