(21197) 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 any body region (except 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 non-central nervous system pathology. This is clinically relevant as it may offer an alternative contrast agent with potentially improved safety or efficacy profiles for patients undergoing MRI.

Secondary objectives include:

• To demonstrate non-inferior diagnostic performance of gadoquatrane compared to macrocyclic GBCAs.
• To demonstrate superior efficacy of gadoquatrane compared to unenhanced MRI.
• To describe diagnostic performance based on contrast-enhanced MRIs with gadoquatrane compared to macrocyclic GBCAs.
• To describe efficacy based on contrast-enhanced MRIs with gadoquatrane compared to macrocyclic GBCAs.
• To evaluate the number of lesions with gadoquatrane-enhanced MRI compared to unenhanced imaging and to macrocyclic GBCAs.
• To demonstrate 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 **399 participants** who are being evaluated for the efficacy of gadoquatrane in contrast enhancement during magnetic resonance imaging (MRI) for non-central nervous system pathology. The study population includes both **male and female subjects** aged 18 years and older, with a clinical indication for a contrast-enhanced MRI. Participants are required to have a known or suspected pathology in any body region except the central nervous system, such as the head and neck, thorax, abdomen, pelvis, or extremities. The trial includes individuals who can undergo study-related procedures, including two contrast-enhanced MRI examinations. Female participants must adhere to local contraceptive regulations and should not be pregnant or breastfeeding. The trial population was selected based on their ability to undergo the necessary procedures and their clinical need for contrast-enhanced MRI, ensuring a diverse representation of individuals with varying pathologies. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, controlled, crossover Phase III study to evaluate the efficacy and safety of **gadoquatrane** compared to approved macrocyclic gadolinium-based contrast agents (GBCAs) in magnetic resonance imaging (MRI) for non-central nervous system pathology. The trial aims to demonstrate the non-inferior efficacy of gadoquatrane. Participants will be randomly assigned to receive either gadoquatrane or a comparator GBCA, with each participant undergoing two contrast-enhanced MRI examinations. The trial is expected to last until November 2024, with recruitment starting in August 2023.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, clinical indication for contrast-enhanced MRI, and ability to undergo study-related procedures. Participants must be at least 18 years old and meet specific health criteria. The inclusion visit will be followed by two MRI visits, where participants will receive either gadoquatrane or a comparator GBCA. The end-of-study visit will conclude the trial, during which final assessments and evaluations will be conducted.

The expected length of participant involvement is approximately two months, with the maximum treatment period being two days. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any situation where continued participation is deemed unsafe by the investigator. The primary endpoint involves the assessment of three visualization parameters by a blinded independent central review (BICR), while secondary endpoints include sensitivity and specificity for lesion detection and the overall diagnostic clinical value of the MRI examinations.

The clinical trial involves the administration of **Gadoquatrane**, a chemical compound used as the experimental medication. It is provided in the form of a **solution for injection** and is administered **intravenously**. The dosage is set at 0.04 mmol per kilogram of body weight, with a maximum total dose of 0.08 mmol. The treatment period is limited to a maximum of 2 days. This compound is identified by the sponsor product code BAY 1747846 and is produced by Bayer AG. The primary objective of the trial is to evaluate the efficacy and safety of Gadoquatrane in comparison to other macrocyclic gadolinium-based contrast agents (GBCAs).

In addition to the experimental medication, the trial includes the use of three comparator treatments: **Gadoteric Acid**, **Gadoteridol**, and **Gadobutrol**. These are all macrocyclic GBCAs, provided in the pharmaceutical form PHF00231MIG, and are also administered **intravenously**. Each of these comparator agents is dosed at 0.1 mmol per kilogram of body weight, with a maximum total dose of 0.2 mmol. The treatment period for these agents is similarly limited to a maximum of 2 days. These comparator treatments are used to establish a baseline for evaluating the non-inferiority of Gadoquatrane in terms of efficacy and safety.

The efficacy of the investigational product, **gadoquatrane**, will be assessed in a multicenter, randomized, prospective double-blind, crossover Phase 3 clinical trial. The primary objective is to demonstrate the non-inferior efficacy of gadoquatrane compared to approved macrocyclic gadolinium-based contrast agents (GBCAs) in adults with known or suspected pathology of any body region, excluding the central nervous system (CNS). The primary endpoints for efficacy evaluation include 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 blinded evaluation of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs by a Blinded Independent Central Review (BICR).

Secondary endpoints include sensitivity and specificity for lesion detection, overall diagnostic clinical value, and confidence in diagnosis. These will be evaluated using both combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs. The assessments will be conducted by both BICR and the investigator. The trial will also evaluate the number of lesions and enhancing lesions observed, as well as the number and intensity of treatment-emergent adverse events, including serious adverse events, following the administration of gadoquatrane compared to macrocyclic GBCAs. The efficacy assessments will be conducted at specified time points, ensuring a comprehensive evaluation of the investigational product's performance in the clinical setting.