Comparison of Gadovist 75% Standard Dose to Dotarem at Full Standard Dose

Study Overview
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Brief Summary
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The study was conducted to gain knowledge about a new dose of a diagnostic drug that is used for contrast-enhanced Magnetic Resonance Imaging (MRI) of the human central nervous system (CNS). MRI can visualize the anatomy of the body and is used to detect medical conditions. Diagnostic drugs like gadobutrol and gadoterate contain an element called gadolinium that is applied to improve the analysability of MRI-images. The purpose of this study was to examine if contrast-enhanced MRI using a reduced dose of the gadolinium-based contrast agent gadobutrol delivers images of similar quality to those obtained when a full dose of the gadolinium-based contrast agent gadoterate was used.

Detailed Description
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The study was an open-label, multi-center, comparative, cross-over trial in adult patients with known or highly suspected CNS pathology who were referred for imaging of the CNS. The primary objective of the study was to demonstrate the non-inferiority of gadobutrol (0.075 mmol/ kg body weight) to gadoterate (0.1 mmol/ kg body weight).

Official Title
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LowEr Administered Dose With highEr Relaxivity: Gadovist vs Dotarem (LEADER 75)

Conditions
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Magnetic Resonance Imaging

Intervention / Treatment
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* Drug: Gadoterate (Dotarem/Clariscan)
* Drug: Gadobutrol (Gadavist/Gadovist, BAY86-4875)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known or highly suspected central nervous system (CNS) pathology referred for contrast-enhanced MRI of the CNS. Glomerular filtration rate (eGFR) value ≥ 60 mL/min/1.73m2 derived from a serum creatinine result within four weeks prior to the first study MRI. Women with negative urine pregnancy test within 1 hour prior to the administration of gadoterate (the first MRI). Exclusion Criteria: No enhancing lesion visible on the gadoterate-enhanced MRI scan. Pregnancy or breastfeeding. Severe cardiovascular disease

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: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1_Suspected CNS-lesion<br>Patients with suspected or confirmed CNS-lesions underwent unenhanced MRI, and contrast-enhanced MRI after gadoterate injection. | Drug: Gadoterate (Dotarem/Clariscan)<br>* Patients received a single dose of 0.5 molar gadoterate (0.1 mmol per kg body weight) intravenously.<br>* Other names: Gadoterate;|
| Experimental: Arm 2_Confirmed CNS-lesion<br>Patients with gadoterate-confirmed CNS-lesions (subgroup of Arm 1) underwent a second unenhanced MRI, and contrast-enhanced MRI after gadobutrol injection. | Drug: Gadoterate (Dotarem/Clariscan)<br>* Patients received a single dose of 0.5 molar gadoterate (0.1 mmol per kg body weight) intravenously.<br>* Other names: Gadoterate;Drug: Gadobutrol (Gadavist/Gadovist, BAY86-4875)<br>* Patients received a single dose of 1.0 molar BAY86-4875 (0.075 mmol per kg body weight) intravenously.<br>* Other names: Gadobutrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of Lesion Contrast Enhancement | Degree of lesion contrast enhancement is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored up to 5 lesions using image sequences and a 4-point scale (1 - No = Lesion not enhanced; 2 - Moderate = Lesion weakly enhanced; 3 - Good = Lesion clearly enhanced; 4 - Excellent = Lesion clearly and brightly enhanced). | Up to 20 days | 
| Lesion Border Delineation | Lesion border delineation is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded readers scored the delineation of up to 5 lesions using image sequences and a 4-point scale (1 - None = No or unclear delineation; 2 - Moderate = Partial delineation; 3 - Good = Almost clear, but incomplete delineation; 4 - Excellent = Clear and complete delineation). | Up to 20 days | 
| Lesion Internal Morphology | Lesion internal morphology is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored the structure and internal morphology of up to 5 lesions using image sequences and a 3-point scale (1 - Poor = Poor visibility; 2 - Moderate = Partial visibility; 3 - Good = Sufficient visibility) | Up to 20 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Lesions Identified | Number of lesions identified (up to 10) detected by 3 blinded Readers. The mean (SD) number lesions in the Average Reader for gadobutrol and gadoterate in the Full Analysis Set was reported below. | Up to 20 days | 
| Detection of Malignant Disease | The 3 Blinded Readers had to evaluate if the diagnosis resulting from the combined images was malignant disease or not. Each blinded Reader provided a malignant yes/no response. This was compared to the final diagnosis provided by the Investigator. The majority of Readers (2 or 3 Readers agree) was used to calculate sensitivity, specificity, and accuracy - eg. Final Diagnosis - Malignant (Reader 1-yes, Reader 2-no, Reader 3-yes --- Majority Reader yes) - this would be a match for sensitivity. The percentage of sensitivity, specificity, and accuracy of detection of malignant disease detected by 3 blinded Readers, gadobutrol versus gadoterate (Full Analysis Set) is reported below for Majority Readers. | Up to 20 days | 
| Confidence in Diagnosis | Diagnostic confidence detected by 3 blinded Readers, gadobutrol vs gadoterate (Full Analysis Set). Blinded Readers rated their confidence in diagnosis according to a 4-point scale (1 - Not confident; 2 - Somewhat confident; 3 - Confident; 4 - Very confident). Results for the Average Reader are reported below. | Up to 20 days | 
| Image Quality | Comparison of image quality between gadobutrol and gadoterate detected by 3 blinded Readers (Full Analysis Set). Blinded Readers assessed the image quality of gadobutrol- and gadoterate-enhanced images (randomly assigned as left [L] and right [R] image positions) according to a 5-point scale (1- Image R is worse; 2 - Image R is slightly worse; 3- Image R is similar; 4 - Image R is slightly better; 5 - Image R is better). After unblinding of data, the above codes were translated into the following scale: -2 = Gadobutrol image set is worse ; -1 = Gadobutrol image set is slightly worse ; 0 = Image sets are the same ; 1 = Gadobutrol image set is slightly better; 2 = Gadobutrol image set is better. Results for the Average Reader are reported below. | Up to 20 days | 
| Contrast Enhancement Utilizing an Exploratory Overall Contrast Enhancement Estimation Algorithm | Comparison of contrast enhancement utilizing an overall contrast enhancement estimation algorithm (Full Analysis Set). The exploratory algorithm analyzed the overall enhancement by comparing the axial T1w (longitudinal relaxation time-weighted) enhanced images to the T1w unenhanced images. | Up to 20 days | 
| Number of Participants With Treatment-emergent Adverse Events | Number of subjects with treatment-emergent adverse events (TEAEs) (Safety Analysis Set). TEAEs are defined as any AEs that increase in intensity or that are newly developed during the TE period for Study Period 1 or Study Period 2, where TE period for Study Period 1 goes from the first study drug administration in Study Period 1 to 24 hours post-injection, and TE period for Study Period 2 from the first study drug administration in Study Period 2 to 24 hours post-injection. | From the first study drug administration up to 24 hours post injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gadolinium, Contrast enhancement, Central nervous system lesion