Dose Finding Study of Gadavist in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

The primary visualization variables (number [no.] of lesions detected, border delineation, contrast enhancement, internal morphology) were condensed to a composite score (CVS). Each variable was considered a category; the CVS was calculated as: CVS=(No. of categories with increase over precontrast)-(No. of categories with decrease over precontrast). The possible outcomes of the CVS for a participant and each reader were in the range of - 3 to +4. The CVS was averaged across the 3 blinded readers, producing 1 mean CVS per participant. The higher the CVS, the more effective the treatment.

Three blinded readers evaluated the unenhanced MRI sets and the combined unenhanced/gadobutrol-enhanced MRI sets to evaluate the number of lesions, which was then averaged to produce an average reader value.

The blinded readers assessed the degree of contrast enhancement for each lesion on a 4-point scale where 1 = no enhancement and 4 = excellent enhancement, which was then averaged to produce an average reader score.

The blinded readers assessed the delineation for each lesion on a 4-point scale where 1 = none and 4 = excellent, which was then averaged to produce an average reader score.

The blinded readers assessed the degree of information available about internal morphology and structure for each lesion on a 3-point scale where 1 = poor and 3 = good, which was then averaged to produce an average reader score.

CNR between white and gray matter in the perfusion imaging was defined as the signal intensity (SI) difference between white and gray matter divided by the standard deviation of the SI of white matter. An independent radiologist evaluated the gadobutrol-enhanced perfusion MRI for signal intensity.

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for blinded reader (BR) 1.

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for BR 2

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for BR 3

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 1

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 2

The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 3

The gadobutrol-enhanced and unenhanced MRI diagnoses of the average reader were compared to the final diagnosis.

The diagnostic confidence, the level of certainty in a diagnosis, was determined based on the average of the blinded readers.

BR 1 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map.

BR 1 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map.

BR 1 evaluated the visibility of the lesion(s) on the CBF perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the CBF perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the CBF perfusion map.

BR 1 evaluated the visibility of the lesion(s) on the TTP perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the TTP perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the TTP perfusion map.

BR 1 evaluated the visibility of the lesion(s) on the MTT perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the MTT perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the MTT perfusion map.

BR 1 evaluated the visibility of the lesion(s) on the PF perfusion map.

BR 2 evaluated the visibility of the lesion(s) on the PF perfusion map.

BR 3 evaluated the visibility of the lesion(s) on the PF perfusion map.

The independent radiologist determined the uncorrected CBV for each lesion. CBV is the volume of blood in the tissue.

The independent radiologist determined the corrected CBV for each lesion. CBV is the volume of blood in the tissue.

The independent radiologist determined the CBF for each lesion. CBF is the volume of blood passing through tissue per unit of time.

The independent radiologist determined the TTP for each lesion. TTP is the delay between the arrival of the contrast agent bolus arrival time and the peak of the concentration curve.

The independent radiologist determined the MTT for each lesion. The MTT is the time (seconds) for contrast to pass through tissues.

The independent radiologist determined the PF for each lesion

The blinded reader evaluated if artifacts were present on the uncorrected CBV perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time.

The blinded reader evaluated if artifacts were present on the corrected CBV perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time. CBV is the fraction of the tissue volume occupied by the blood.

The blinded reader evaluated if artifacts were present on the CBF perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time

The blinded reader evaluated if artifacts were present on the TTP perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time

The blinded reader evaluated if artifacts were present on the MTT perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time

The blinded reader evaluated if artifacts were present on the PF perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time

The blinded readers gave an estimation of the tumor grade of brain tumors (low grade [I or II] or high grade [III or IV]) in terms of malignancy using the information obtained by perfusion imaging, which was compared to the biopsy sample results

CNR between lesion/gray matter and lesion/white matter in the perfusion imaging was defined as the signal intensity (SI) difference between lesion and gray or white matter divided by the standard deviation of background noise. An independent radiologist evaluated the gadobutrol-enhanced perfusion MRI for signal intensity.