MultiHance (Page 5 of 7)

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of MultiHance.

The results for MultiHance were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats.

MultiHance had no effect on fertility and reproductive performance at IV doses of up to 2 mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells were observed when MultiHance was intravenously administered to male rats at 3 mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were not reversible following 28-day recovery period. The effects were not reported in dog and monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis for dogs (28 days dosing) and monkeys (14 days dosing), respectively).

14  CLINICAL STUDIES

14.1  MRI of the CNS

Adults:MultiHance was evaluated in 426 adult patients in 2 controlled clinical trials of the central nervous system (Study A and Study B), enrolling 217 men and 209 women with a mean age of 52 years (range 18 to 88 years). The racial and ethnic representations were 88% Caucasian, 6% Black, 4% Hispanic, 1% Asian, and 1% other racial or ethnic groups. These trials were designed to compare MultiHance contrast MRI to non-contrast MRI alone. In Study A, patients highly suspected of having a lesion(s) of the CNS based on nuclear medicine imaging, computed tomography (CT), contrast CT, MRI, contrast- MRI, or angiography were randomized to receive two MRI evaluations with 0.05 mmol/kg (n=140) or 0.1 mmol/kg (n=136) of MultiHance. In Study B, patients with known metastatic disease to the CNS were randomized to receive two MRI evaluations with 0.05 mmol/kg (n=74) or 0.1 mmol/kg (n=76) of MultiHance. MRI scans were performed pre-contrast and within 5 minutes after each injection. The studies were designed to evaluate the effect of MultiHance MRI compared to the non-contrast MRI on a lesion level. Pre-contrast, post-contrast, and pre-plus-post contrast images (paired images) were independently evaluated by three blinded readers. The images were evaluated for the following endpoints using a scale from 0 to 4: the degree of lesion border delineation, the degree of visualization of lesion internal morphology, and the degree of lesion contrast enhancement. Lesion counting was also performed for the pre-contrast and paired image sets.

The 0.1 mmol/kg dose of MultiHance demonstrated consistently better visualization for all readers for all visualization endpoints. However, the 0.05 mmol/kg dose of MultiHance provided inconsistent visualization results between readers.

Comparison of pre-contrast versus post-contrast (0.1 mmol/kg) images showed that the mean score differences were significant and favored contrast for subjects in Study B (all subjects with known metastatic lesions) and for subjects with known tumors in Study A. However, the mean score differences between the pre-contrast and post-contrast images were not significant for non-tumor patients in Study A. These negative results may be attributed to a lack of lesion enhancement in non-tumor CNS disease.

Table 4 shows a comparison of paired images (pre-and post-contrast) versus pre-contrast images with respect to the difference in the mean score and with respect to the proportion of lesions read as better, worse, or the same as the pre-contrast MRI images. Table 4 shows that based on a lesion-level analysis 0.1 mmol/kg MultiHance provided a statistically significant improvement for the three structural parameters evaluated. Also, more lesions were seen in the paired images than in the pre-contrast images alone.

(a) Difference of means = (paired mean) — (pre mean)(b) Worse = paired score is less than the pre scoreSame = paired score is the same as the pre scoreBetter = paired score is greater than the pre score* Statistically significant for the mean (paired t test)
Table 4: LESION LEVEL RESULTS OF MRI CENTRAL NERVOUS SYSTEM ADULT STUDIES WITH 0.1 mmol/kg MULTIHANCE
Study A Study B
Reader 1 Reader 2 Reader 3 Reader 1 Reader 2 Reader 3
Endpoints N = 395 N = 384 N = 299 N = 245 N = 275 N = 254
Border Delineation:
Difference of Means (a) 0.8* 0.6* 0.8* 1.8* 1.5* 1.9*
Worse (b)SameBetter 44 (11%)146 (37%)205 (52%) 61 (16%)168 (44%)155 (40%) 57 (19%)89 (30%)153 (51%) 13 (5%)11 (5%)221 (90%) 24 (9%)19 (7%)232 (84%) 15 (6%)18 (7%)221 (87%)
Internal Morphology:
Difference of Means 0.8* 0.6* 0.7* 1.7* 1.4* 2.1*
WorseSameBetter 37 (10%)147 (37%)211 (53%) 63 (17%)151 (39%)170 (44%) 62 (21%)84 (28%)153 (51%) 13 (5%)16 (7%)216 (88%) 26 (10%)22 (8%)227 (82%) 14 (5%)22 (9%)218 (86%)
Contrast Enhancement:
Difference of Means 0.7* 0.5* 0.8* 1.9* 1.3* 1.9*
WorseSameBetter 75 (19%)148 (37%)172 (44%) 74 (19%)152 (40%)158 (41%) 50 (17%)109 (36%)140 (47%) 13 (5%)11 (5%)221 (90%) 32 (12%)21 (7%)222 (81%) 17 (7%)14 (5%)223 (88%)

Pediatric 2 to 17 years
The efficacy and safety of MultiHance were evaluated in 92 pediatric patients with known or highly suspected disease of the central nervous system. MRI scans were performed pre-contrast and within 3 to 10 minutes following the administration of MultiHance 0.1 mmol/kg. Pre-contrast, post-contrast, and pre-plus-post contrast images (paired images) were independently evaluated by three blinded readers on a lesion level. The images were evaluated for the same endpoints as in the adult central nervous system trials using a scale from 0 to 4: the degree of lesion border delineation, the degree of visualization of lesion internal morphology, and the degree of lesion contrast enhancement. Lesion counting was also performed for the pre-contrast and paired image sets. The pre-contrast versus the paired image set was the primary comparison. Forty-nine percent of study subjects were male and the overall mean age was 10.6 years (range 2 to 17 years). The racial and ethnic representations were 77% Caucasian, 13% Asian, 5% Black, and 4% other racial or ethnic groups. MultiHance increased lesion border delineation, lesion internal morphology, and lesion contrast enhancement relative to non-contrast and these results were comparable to those seen in adults.

Pediatrics below 2 yearsA study of 90 pediatric patients younger than 2 years of age was performed which supports extrapolation of CNS efficacy findings from adults and older pediatric patients. Three independent, blinded readers evaluated pre-contrast MRI image sets and paired pre-plus-post-contrast MRI image sets using MultiHance and rated the images according to three co-primary endpoints at a lesion level for the primary analysis. Two of the three readers reported improvement in the paired image sets in each of the three co-primary endpoints of lesion border delineation, visualization of lesion internal morphology, and lesion contrast enhancement.

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