Clinical Efficacy of Reduced Dose Gadobutrol Versus Standard Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

Abstract

Background: Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol s higher T1 relaxivity, reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as standard gadoterate dose. Objective: To demonstrate that efficacy of 25%-reduced dose of gadobutrol (rd-gadobutrol) is non-inferior to 100%-standard-dose of gadoterate (sd-gadoterate) for contrast-enhanced MRI of the CNS. Methods: In this international, prospective, multicenter, open-label, cross-over trial (LEADER-75), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with sd-gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with rd-gadobutrol (0.075 mmol/kg) was performed within 15 days. Three radiologists independently reviewed images to score three primary efficacy measures (subjective lesion enhancement, lesion border delineation, lesion internal morphology); primary non-inferiority analysis used readers mean scores. Non-inferiority of rd-gadobutrol to sd-gadoterate for primary efficacy measures was defined as difference in score between rd-gadobutrol and unenhanced images achieving at least 80% of difference in score between sd-gadoterate and unenhanced images. Post-hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. Results: The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5±13.5 years). Improvement of rd-gadobutrol over unenhanced images was non-inferior to improvement of sd-gadoterate over unenhanced images using 20% non-inferiority margin for all three primary efficacy measures using mean readings (p≤.025). In post-hoc analysis, mean reading for the three primary efficacy measures differed by less than 1% between rd-gadobutrol and sd-gadoterate, supporting equivalence of all measures using a narrow ±5% margin (p≤.025). Total lesions detected by mean reading was 301 for rd-gadobutrol versus 291 for sd-gadoterate. Mean confidence was 3.3±0.6 for rd-gadobutrol versus 3.3±0.6 for sd-gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for rd-gadobutrol and sd-gadoterate. Reader preference was not different (95% CI [-0.10, 0.11]). Conclusion: A 25%-reduced dose of gadobutrol is non-inferior to sd-gadoterate for contrast-enhanced brain MRI. Clinical Impact: Use of rd-gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations.