Phase III, Multicenter, Double-blind, Randomized, Crossover Study to Compare MultiHance with Magnevist in Contrast-Enhanced Magnetic Resonance Imaging (MRI) of the Breast.

Magnetic resonance imaging (MRI) is rapidly emerging as a clinically useful
examination for the evaluation of breast lesions because of its value in soft
tissue assessment. It is well accepted that the use of intravenous MRI
contrast agents contributes to the detection as well as the characterization
and delineation of breast lesions. Preliminary investigations with MULTIHANCE
in breast MRI have demonstrated promising results. With the experience
gathered from a study in 189 subjects, the 0.1 mmol/kg dose appeared superior
to the 0.05 and 0.2 mmol/kg doses in both lesion detection and
characterization. Based on these results, the optimal dose selected for breast
studies is 0.1 mmol/kg. No safety concerns were raised in subjects receiving up
to a dose of 0.2 mmol/kg MULTIHANCE.

Primary Objective: To show superiority of a 0.1 mmol/kg dose of MULTIHANCE over
a 0.1 mmol/kg dose of MAGNEVIST for breast MRI in terms of sensitivity for the
diagnosis of malignant lesions compared with histopathology. Secondary
Objectives: a)To compare the 0.1 mmol/kg dose of MULTIHANCE with the 0.1
mmol/kg dose of MAGNEVIST for breast MRI for the diagnosis of breast cancer
compared with truth standard findings in terms of: sensitivity, specificity,
accuracy, positive predictive value and negative predicative value at region
level, at breast level; and at subject level; and inter-reader agreement in
determining the nature of the lesions; b)To compare the 0.1 mmol/kg dose of
MULTIHANCE with the 0.1 mmol/kg dose of MAGNEVIST for breast MRI in terms of:
qualitative and quantitative assessment of contrast between breast lesions and
normal parenchyma, Qualitative assessment of border delineation of lesions, and
global diagnostic preference of the blinded readers; c)To confirm the
previously established safety profile of a single dose (0.1 mmol/kg) of
MULTIHANCE in comparison with MAGNEVIST at the same dose for MRI of the breast.

This will be a Phase III, multicenter, randomized, double-blind, crossover
study aimed at within subject comparison of 0.1 mmol/kg MULTIHANCE and 0.1
mmol/kg MAGNEVIST during breast MRI examinations in subjects with suspected or
known breast cancer in terms of diagnostic and technical performance in the
diagnosis and evaluation of malignant and benign breast lesions as determined
by histopathology. In case of benign lesion(s) not confirmed at histopathology,
ultrasound and/or mammography will be performed at 6-month (+ or - 2 months)
after Exam 2. Each subject will undergo two breast MRI examinations (Exam 1 and
Exam 2) with a minimum interval of 48 hours, but no longer than 14 days between
the examinations, using commercially available equipment at 1.5 Tesla (T)
magnetic field strength. All MRI image sets of the subjects included in the
study will be collected for both on-site and independent off-site evaluations.
The Investigators at each site will evaluate the MRI images from Exam 1 and
Exam 2, respectively. An additional independent Investigator, other than the
MRI reader, will provide all truth standard findings. Off-site assessments of
MRI will be conducted by 3 independent experienced radiologists unaffiliated
with the study sites and fully blinded to all clinical and radiological
information of the subjects and the IP used in each respective MRI
examination. After the off-site blinded read is completed, adjudication will
be performed by an additional independent experienced radiologist (adjudicator)
unaffiliated with the study sites.

In Exam 1, 50 % of the patients start with MultiHance, the others with
Magnevist. In Exam 2 the patients get the other contrast liquid in comparison
with Exam 1.

Both MULTIHANCE and MAGNEVIST, have very good and similar safety profiles. MRI
is a standard non-invasive clinical diagnostic imaging technique that does not
involve ionizing radiation. The risk of undergoing MRI examination is extremely
low if the standard precautions and procedures are to be followed and subjects
with contraindications to MRI or test agents are excluded from this study.
Expected benefits from the MRI examinations include more reliable diagnosis
than conventional imaging techniques such as mammography or ultrasonography..
MRI contrast agents will be injected intravenously which may carry a common
risk related with venipuncture, such as discomfort and/or bruising at the site
of puncture.
It is not possible to predict whether or not any direct benefit may result from
the participation in this study. Diagnostic contrast agents are usually
studied in single-administration trials. However, the crossover trials
conducted so far with MULTIHANCE in comparison with MAGNEVIST have not shown
any overall increased incidence of adverse events. Therefore, no substantial
added risk is foreseen when two contrast-enhanced MRI examinations are
performed on the same subject with a minimum interval of 48 hours.
Conversely, on the basis of the recent results of intra-individual comparison
of MULTIHANCE with MAGNEVIST in breast MRI, some benefit due to additional
imaging with MULTIHANCE and careful diagnostic evaluation could be expected for
some subjects of the present study in terms of more accurate detection or
diagnosis of breast cancer.