Patients with known or suspected disease of the supra-aortic arteries (for evaluation up to but excluding the basilar artery) were enrolled in Study C, and patients with known or suspected disease of the renal arteries were enrolled in Study D. In both studies, non-contrast, 2D time-of-flight (ToF) magnetic resonance angiography (MRA) was performed prior to gadobutrol injection MRA using a single intravenous injection of 0.1 mmol/kg. The injection rate of 1.5 mL/second was selected to extend the injection duration to at least half of the imaging duration. Imaging was performed with parallel-channel, 1.5T MRI devices and an automatic bolus tracking technique to trigger the image acquisition following gadobutrol injection administration using elliptically encoded, T1-weighted, 3D gradient-echo image acquisition and single breath hold. Three central readers blinded to clinical information interpreted the ToF and gadobutrol injection MRA images. Three additional central readers interpreted separately acquired computed tomographic angiography (CTA) images, which were used as the standard of reference (SoR) in each study.

The studies included 749 subjects: 457 were evaluated in Study C, with an average age of 68 (range 25–93); 64% were male; 80% white, 28% black, and 16% Asian. An additional 292 subjects were evaluated in Study D, with an average age of 55 (range 18–88); 54% were male; 68% white, 7% black, and 22% Asian.

Efficacy was evaluated based on anatomical visualization and performance for distinguishing between normal and abnormal anatomy. The visualization metric depended on whether readers selected, “Yes, it can be visualized along its entire length...” when responding to the question, “Is this segment assessable?” Twenty-one segments in Study C and six segments in Study D were presented per subject to each reader. The performance metrics, sensitivity and specificity, depended on digital caliper-based quantitation of arterial narrowing in visualized, non-occluded, abnormal-appearing segments. Significant stenosis was defined as at least 70% in Study C and 50% in Study D. Performance of gadobutrol injection MRA compared to ToF MRA was calculated using an imputation method for non-visualized segments by assigning them as a 50% match with SoR and a 50% mismatch. Performance of gadobutrol injection MRA compared to a pre-specified threshold of 50% was calculated after excluding non-visualized segments. Measurement variability and visualization of accessory renal arteries was also evaluated.

Results were analyzed for each of the three central readers.

GAD MRA = Post-contrast gadobutrol injection Magnetic Resonance Angiography, ToF = Non-contrast 2D-Time of Flight.

For all three supra-aortic artery readers in Study C, the lower bound of confidence for the sensitivity of gadobutrol injection MRA did not exceed 54%. For all three renal artery readers in Study D, the lower bound of confidence for the sensitivity of gadobutrol injection MRA did not exceed 46%.

###  Measurement Variability

For both MRA and CTA, readers varied in the quantity of narrowing they assigned to the same arterial segments. Table 11 shows the percentage of patients in whom the measurement range was 30% or greater for the left or right internal carotid and proximal renal artery segments. There were approximately four measurements per patient segment, one from the site and three central readers. Measurement variability was high for both CTA and MRA, but numerically lower for gadobutrol injection compared to non-contrast ToF MRA.

###  Visualization of Accessory Renal Arteries for Surgical Planning and Renal Donor Evaluation (Study D only)

Of 1752 main arteries visualized by the central CTA readers, 266 (15%) were also associated with positive visualization of at least one accessory (duplicate) artery. With the central MRA readers, the comparable rates were 232 of 1752 (13%) for gadobutrol MRA compared to 53 of 1752 (3%) for ToF MRA.