A Study to Compare How Well Gadoquatrane Works and Its Safety With an Already Available Contrast Agent for MRI in People With Any Known or Suspected Problems of the Body (Except Brain or Spinal Cord-related Problems)

Study Overview
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Brief Summary
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Researchers are looking for a better way to help people with any known or suspected problems (except brain or spinal cord-related problems) scheduled for a contrast-enhanced Magnetic Resonance Imaging (MRI). MRI is used by doctors to create detailed images of the inside of the body to identify health problems. Sometimes doctors need to inject contrast agent into a patient's vein to perform a contrast-enhanced MRI (CE-MRI). Such CE-MRI may help identify certain health problems or improve the evaluation. The contrast agents commonly used in MRI are gadolinium-based contrast agents (GBCAs). GBCAs contain a rare earth element called gadolinium (Gd). Gadoquatrane is a new contrast agent under development with a lower amount of Gd needed per CE-MRI. The main purpose of this study is to learn whether CE-MRI scans with gadoquatrane work better than MRI scans without the use of a contrast agent (GBCA). The researchers will compare the ability to detect known or suspected problems (except brain or spinal cord-related problems) with gadoquatrane-MRI scans to plain-MRI scans without the use of a contrast agent. The participants will undergo 2 MRI scans, one with gadoquatrane and one with currently used GBCA. Both contrast agents will be injected into the vein. Each participant will be in the study for between 6 and 42 days with up to 7 doctor visits. At the start or during the study, the doctors and their study team will: take blood and urine samples do physical examinations check blood pressure and heart rate review the MRI scans obtained in the study and decide on the diagnosis ask the participants questions about how they are feeling and what adverse events they are having. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events, irrespective if they think it is related or not to the study treatments.

Official Title
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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)

Conditions
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Contrast Enhancement in Magnetic Resonance Imaging, Non-central Nervous System Pathology

Intervention / Treatment
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* Drug: Gadoquatrane (BAY1747846)
* Drug: Gadobutrol
* Drug: Gadoterate meglumine
* Drug: Gadoteridol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be >= 18 years of age inclusive, at the time of signing the informed consent form Participants with a clinical indication for a contrast-enhanced MRI (including magnetic resonance angiography [MRA]), with any approved standard of care macrocyclic GBCA with proven efficacy, safety and tolerability in clinical routine CE-MRI/MRA (gadobutrol, gadoterate meglumine/ gadoteric acid or gadoteridol) that is used at the site for the indication, with known or suspected pathology of any body region, e.g. head and neck (except central nervous system [CNS]), thorax (including e.g. breast, heart, chest wall), abdomen (including e.g. liver, kidney, pancreas), pelvis (including e.g. prostate, uterus, ovaries), extremities (including upper and lower. Participants who can undergo study-related procedures, including 2 contrast-enhanced MRI examinations (one with gadoquatrane and one with a comparator macrocyclic GBCA), as per participant and Investigator's judgement Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of nonchildbearing potential (WONCBP) OR Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method during the study intervention period (at a minimum of 24 hours after the last dose of study intervention). Exclusion Criteria: Considered clinically unstable or has a concurrent/concomitant condition that may significantly alter image comparability between the 2 study MRIs or between study parameters (e.g. safety, pharmacokinetics [PK] parameters) or would not allow participation for the full planned study period, in the judgement of the investigator Participants presenting with severe renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2, derived from a serum creatinine sample obtained within 48 hours prior to the first contrast agent injection in the study Participants with acute kidney injury (i.e., acute renal failure), regardless of eGFR History of moderate to severe allergic-like reaction to any GBCA Bronchial asthma considered unstable and/or requiring medical treatment Receipt of any contrast agent < 72 h prior to the study MRIs or planned to receive any contrast agent during the trial until 24 h +/- 4 h after the second study MRI Planned or expected interventional diagnostic or therapeutic procedure (e.g. biopsy or surgery in the region of interest) or change in treatment (e.g. start of chemotherapy or antiangiogenic therapy, significant change in corticosteroids dose) that may significantly alter image comparability between the 2 MRIs or other study parameters (i.e. safety/adverse events [AEs] [e.g. confounding AEs or safety events due to surgery or chemotherapy], PK parameters), from the first study MRI up to 24 h after the second study MRI Has received any investigational product within 30 days, or within 5 times half-life of the investigational product, whatever is shorter, prior to or concurrent with this study Contraindications to the administration of macrocyclic GBCAs (depending on local product label), or history of adverse reaction to gadoquatrane Any contraindication to MRI examinations based on institution policy and investigator's clinical judgement (e.g. some metallic implants or active implants)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The site staff in charge of the preparation and administration of study intervention will be unblinded and will not be involved in any evaluation of safety and efficacy. The site staff in charge of conducting all other study procedures as per the schedule of activities (SoA) will remain blinded to the study intervention administered.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gadoquatrane - Approved Macrocyclic GBCA<br>Participants will receive one intravenous injection of gadoquatrane during MRI in Period 1, followed by one intravenous injection of any approved macrocyclic GBCA during MRI in Period 2. | Drug: Gadoquatrane (BAY1747846)<br>* 0.04 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>Drug: Gadobutrol<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>Drug: Gadoterate meglumine<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>* Other names: Gadoteric acid;Drug: Gadoteridol<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>|
| Experimental: Approved Macrocyclic GBCA - Gadoquatrane<br>Participants will receive one intravenous injection of any approved macrocyclic GBCA during MRI in Period 1, followed by one intravenous injection of gadoquatrane during MRI in Period 2. | Drug: Gadoquatrane (BAY1747846)<br>* 0.04 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>Drug: Gadobutrol<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>Drug: Gadoterate meglumine<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>* Other names: Gadoteric acid;Drug: Gadoteridol<br>* Approved standard of care macrocyclic GBCA, 0.1 mmol Gd/kg body weight, solution for intravenous injection, single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visualization parameter contrast Enhancement assessed by separate blinded evaluation of unenhanced and combined pre- and post-gadoquatrane MRI, by a BICR | Contrast Enhancement will be assessed on a 4-point scale (1/No: not enhanced, 2/Moderate: weakly enhanced, 3/Good: clearly enhanced, 4/Excellent: clearly and brightly enhanced). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging | 1 day procedure | 
| Visualization parameter delineation assessed by separate blinded evaluation of unenhanced and combined pre- and post-gadoquatrane MRI, by a BICR | Delineation will be assessed on a 4-point scale (1/No: no or unclear delineation, 2/Moderate: some aspects of delineation, 3/Good: almost clear but not complete, 4/Excellent: clear and complete delineation). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging | 1 day procedure | 
| Visualization parameter morphology assessed by separate blinded evaluation of unenhanced and combined pre- and post-gadoquatrane MRI, by a BICR | Morphology will be assessed on a 3-point scale (1/Poor: no or poorly evaluable, 2/Moderate: partially evaluable, 3/Good: sufficiently evaluable). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging | 1 day procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visualization parameter contrast assessed by separate blinded evaluation of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | Contrast Enhancement will be assessed on a 4-point scale (1/No: not enhanced, 2/Moderate: weakly enhanced, 3/Good: clearly enhanced, 4/Excellent: clearly and brightly enhanced). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Visualization parameter delineation assessed by separate blinded evaluation of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | Delineation will be assessed on a 4-point scale (1/No: no or unclear delineation, 2/Moderate: some aspects of delineation, 3/Good: almost clear but not complete, 4/Excellent: clear and complete delineation). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Visualization parameter morphology assessed by separate blinded evaluation of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | Morphology will be assessed on a 3-point scale (1/Poor: no or poorly evaluable, 2/Moderate: partially evaluable, 3/Good: sufficiently evaluable). BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Sensitivity for the detection of lesions of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Specificity for the detection of lesions of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| The overall diagnostic clinical value of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs | The overall diagnostic clinical value is composed of 2 elements and based on: i.the evaluation of diagnostic descriptive imaging features adapted from radiologic reporting standards (detection/exclusion of enhancing pathology; location, extent, and pattern of enhancement) on a 5-point scale (1- no diagnostic clinical value from contrast enhancement, 2- poor diagnostic clinical value from contrast enhancement, 3- moderate diagnostic clinical value from contrast enhancement, 4- good diagnostic clinical value from contrast enhancement, 5- excellent diagnostic clinical value from contrast enhancement), by the BICR and the Investigator; ii. the evaluation of patient management based on the diagnostic reporting recommendations (i.e., likely diagnosis), by the Investigator. BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging | 1 day procedure | 
| Sensitivity for the detection of malignant lesions of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs assessed by BICR and the investigator | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Specificity for the detection of malignant lesions of combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs assessed by BICR and the investigator | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Diagnoses from combined pre- and post- gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs by the Investigator | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Confidence in diagnosis combined pre- and post- gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs by BICR and by Investigator | The degree of confidence will be rated on a 4-point scale: 1 = Not confident， 2 = Somewhat confident, 3 = Confident, 4 = Very confident. BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Number of lesions seen on unenhanced MRI image set and combined pre- and post-gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Number of enhancing lesions seen on combined pre- and post- gadoquatrane MRI and combined pre- and post-comparator MRI with macrocyclic GBCAs, by a BICR | BICR = blinded independent central read / blinded independent central readers; MRI = magnetic resonance imaging; GBCAs = gadolinium-based contrast agents | 1 day procedure | 
| Number of participants with treatment emergent adverse events, including number of serious adverse events, after administration of gadoquatrane compared to macrocyclic GBCAs reported by the investigator | GBCAs = gadolinium-based contrast agents | Within 24 ± 4 hours after administration of gadoquatrane or any approved macrocyclic GBCAs | 
| Number of participants with treatment emergent adverse events, including number of serious adverse events, per intensity after administration of gadoquatrane compared to macrocyclic GBCAs reported by the investigator | GBCAs = gadolinium-based contrast agents | Within 24 ± 4 hours after administration of gadoquatrane or any approved macrocyclic GBCAs |