Gadobutrol Enhanced MRA of the Supra-aortic Vessels

Study Overview
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Brief Summary
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Subjects referred for a routine CTA (computed tomography angiography) or MRA (magnetic resonance angiography) will be invited to participate in the study and subjects will be involved in the study for between 2 and 12 days. Two to three visits to the study doctor will be required. This study will compare the diagnostic results of Gadobutrol enhanced MRA images with MRA images taken without contrast agent using images from a CTA as the standard of reference, which may have been performed up to 60 days prior to enrolment. If a CTA has not been performed in this prior time period, a CTA is required for the study. MRA and CTA images will be collected for an independent review (blinded read).

Official Title
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Multicenter, Open-label Study to Evaluate the Safety and Efficacy (by Blinded Reading) of Contrast-Enhanced Magnetic Resonance Angiography (MRA) After a Single Intravenous Injection of 0.1 mmol/kg Gadobutrol in Subjects With Known or Suspected Vascular Disease of the Supra-aortic Vessels

Conditions
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Carotid Stenosis

Intervention / Treatment
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* Drug: Gadobutrol (Gadovist, BAY86-4875)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, aged 18 years and older Any of the following: Known or suspected supra-aortic arterial disease based on: Prior stroke Transient ischemic attack (TIA) Amaurosis Fugax (transient monocular blindness) Referred for evaluation of any supra-aortic vessel (for clinically significant stenosis) Follow-up for a stent in a supra-aortic vessel Prior imaging study (CTA or ultrasound) showing ≥ 50% stenosis of a supra-aortic vessel segment (within 60 days before consent). The proportion of subjects with positive disease (determined by the investigator, based on CTA or ultrasound) will be monitored during the study, and enrolment may be further restricted to require ≥ 70% stenosis to ensure that overall there are an adequate number of subjects with clinically significant disease for the evaluation of study endpoints. Willingness to undergo the routine Contrast Enhanced Magnetic Resonance Angiography [CE MRA] examination with gadobutrol Willingness and ability to follow directions and complete all study procedures specified in the protocol Females of childbearing potential only: Negative pregnancy test on the day of the MRA before the administration of study drug Exclusion Criteria: Pregnant or nursing (including pumping for storage and feeding) Received any other investigational product or participation in any other clinical trial within 30 days before enrollment into this study Previous enrollment into this study or into any other Bayer sponsored study using gadobutrol Contraindication to the MRA examinations (e.g. inability to hold breath; severe arrhythmias; very low cardiac output, severe claustrophobia, defibrillators or other metallic devices not approved for MRI) Contraindication to the use of Gd-containing contrast agents (including subjects with suspicion for or known to have Nephrogenic Systemic Fibrosis [NSF]) History of severe allergic or anaphylactoid reaction to any allergen including drugs and contrast agents Received any contrast agent within 72 hours before the study MRA, or scheduled receipt of any contrast agent within 24 hours after the study MRA (Note: This applies also to a CTA potentially scheduled during the course of the study.) Estimated glomerular filtration rate (eGFR) value < 30 ml/min/1.73 m2 derived from a serum creatinine result within 2 weeks before the gadobutrol injection. Any subject on hemodialysis or peritoneal dialysis is excluded from participation. Use the value obtained prior to and closest to the time of the MRA, if there are multiple creatinine values. (Do not use the core lab value if not available prior to the MRA.) Acute renal insufficiency of any intensity, either due to hepato-renal syndrome or occurring in the peri-operative liver transplantation period Severe cardiovascular disease (e.g. acute myocardial infarction [< 14 days], unstable angina, congestive heart failure New York Heart Association class IV) or known long QT syndrome Suspected clinical instability or unpredictability of the clinical course during the study period (e.g. due to previous surgery) Scheduled or potentially expected for the period between the CTA and gadobutrol MRA: Any procedure that may alter the MRA or CTA interpretation, or Any interventional or surgical procedure involving the supra-aortic vessels

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Drug: Gadobutrol (Gadovist, BAY86-4875)<br>* A single bolus injection of approx. 0.1mmol/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA | Each vascular segment was visualized using unenhanced MRA and gadobutrol-enhanced MRA, characterized by the on-site investigators, three independent blinded readers (BR) (BR 1, BR 2 and BR 3) and majority readers (the outcome determined by at least two of the blinded readers). A segment was assessable if it was visualized along its entire length and if any region of stenosis, was measured reliably. There were 21 segments of the supra-aortic arteries assessed per participant. | Images were taken pre-injection and post-injection | 
| Sensitivity for Detection of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA | Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the standard of reference (SoR) (computed tomographic angiography [CTA]; blinded readers). This was determined using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded. | Images were taken pre-injection and post-injection | 
| Specificity for Exclusion of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA | Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the SoR (CTA; blinded readers). This was determined using the NASCET criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded. | Images were taken pre-injection and post-injection | 
| Minimum Gadobutrol Performance for Sensitivity: Sensitivity > 50% | Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter. | Images were taken pre-injection and post-injection | 
| Minimum Gadobutrol Performance for Specificity: Specificity > 50% | Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter. | Images were taken pre-injection and post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vessel Diameter (Millimeter [mm]) at the Normal Point and the Narrowest Point in Gadobutrol-Enhanced MRA, Unenhanced MRA and CTA Images | The segment reduction in diameter (DIA) of greater than 10% was considered abnormal and measured. The diameter of each of these abnormal segments was measured using electronic calipers (perpendicular to the long axis of the vessel) at the point of most severe stenosis within each segment. Mean of vessel diameters was calculated by segment separately for CTA and MRA readers. For ease of expression, the following abbreviations will be used: Diameter (DIA), Blinded Reader (BR), Clinical Investigator (CI). | Images were taken pre-injection and post-injection | 
| The Percentage of Segments With Artifacts Presence | Artifacts were collected for the MRA images on a segmental basis. | Images were taken pre-injection and post-injection | 
| Types of Artifacts on a Segment Basis by Blinded Reader 1 | The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact). | Images were taken pre-injection and post-injection | 
| Types of Artifacts on a Segment Basis by Blinded Reader 2 | The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact). | Images were taken pre-injection and post-injection | 
| Types of Artifacts on a Segment Basis by Blinded Reader 3 | The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact). | Images were taken pre-injection and post-injection | 
| The Percentage of Location of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA | Location within a segment was based on the point of greatest stenosis and was recorded for stenosis >=70% (including occlusions) as: - At the bifurcation or proximal origin of a segment (occlusion proximal to the origin of the segment); - Within 5 mm of the bifurcation or proximal origin of a segment; - Beyond 5 mm from the bifurcation or proximal origin of a segment. | Images were taken pre-injection and post-injection | 
| Length of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA | The length of stenosis was based on the most proximal (first point) in a segment where a stenosis exceeded 10% and the most distal point (last point) in the segment where a stenosis exceeded 10%. If a stenosis spanned more than one segment then the measurement was only included to the beginning or end (boundary) of the segment being evaluated. If there was no stenosis of >=70% in a segment then the length was designated as 0. | Images were taken pre-injection and post-injection | 
| The Percentage of Presence of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease | Each segment was assessed for secondary signs of stenosis for diagnosis of clinically significant disease. The following indicators were considered for the MRA studies: - post-stenotic dilation or ulceration (segmental), - post-stenotic signal dropout, narrowing and intensity reduction, and - thrombus. Each of the three parameters were assessed as present or absent in the region distal to the stenosis. If they were found in any segment distal to the stenosis then they were assessed as present. | Images were taken pre-injection and post-injection | 
| Type of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease | Each segment was assessed for secondary signs of stenosis for diagnosis of clinically significant disease. The following indicators were considered for the MRA studies: - post-stenotic dilation or ulceration (segmental), - post-stenotic signal dropout, narrowing and intensity reduction, and - thrombus. Each of the three parameters were assessed as present or absent in the region distal to the stenosis. If they were found in any segment distal to the stenosis then they were assessed as present. If there were tandem (serial) stenosis in a vessel then the secondary signs were assigned to the stenosis of >=70% that was proximal and closest in proximity to the secondary sign. | Images were taken pre-injection and post-injection | 
| Diagnostic Confidence by the Blinded Readers Using Gadobutrol-Enhanced MRA and Unenhanced MRA | Diagnostic confidence was evaluated to determine the level of certainty that the blinded readers assigned to a diagnosis for each segment. This was defined as the degree of confidence that the information on the MRA images represented the true and complete clinical picture of a particular segment. The degree of confidence was rated on a 4-point scale: 1 = Not confident, 2 = Somewhat confident, 3 = Confident, and 4 = Very confident. | Images were taken pre-injection and post-injection | 
| The Percentage of Participants With Additional Imaging Studies Recommended by the Blinded Readers and the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images | A measure of diagnostic value was the reduction in the number of additional diagnostic imaging studies recommended/ordered. The clinical investigators and the blinded readers were asked if they would have recommended an additional imaging study for each participant and was recorded. | Images were taken pre-injection and post-injection | 
| Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 1 | An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study. | Images were taken pre-injection and post-injection | 
| Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 2 | An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study. | Images were taken pre-injection and post-injection | 
| Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 3 | An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study. | Images were taken pre-injection and post-injection | 
| Types of Additional Imaging Studies Recommended by the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images | An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study. | Images were taken pre-injection and post-injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Males and females aged 18 years or older, Stroke, Transient Ischemic Attack (TIA), Supra-aortic vascular disease, MRA, CTA