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, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the 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 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings (p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin (p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.