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Magnetic Resonance Insights
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Efficacy and Safety of Gadobutrol (1.0 M) versus Gadopentetate
Dimeglumine (0.5 M) for Enhanced MRI of CNS Lesions:
A Phase III, Multicenter, Single-Blind, Randomized Study
in Chinese Patients
Zonghui Liang1,2, Lin Ma3, Dehang Wang4, Yi Huan5, Ping Li6, Jun Yu1, Zhenwei Yao1, Shuang Chen1,
Huijin He1, Xiaoyuan Feng1 and Josy Breuer7
Radiology Department, Huashan Hospital, Fudan University, Shanghai, China. 2Radiology Department, Shanghai Jing’an
District Centre Hospital (Fudan University Huashan Hospital Jing’an Branch), Shanghai, China. 3Radiology Department,
Chinese PLA 301st Hospital, Beijing, China. 4Radiology Department, The People’s Hospital of Jiangsu Province, Jiangsu,
China. 5Radiology Department, Xijing Hospital, Shanxi, China. 6Bayer Healthcare Company Ltd., Beijing, China. 7Bayer
Schering Pharma AG, Berlin, Germany. Corresponding author email: [email protected]
1
Abstract: The aim of this study was to compare the efficacy and safety of macrocyclic gadobutrol (1.0 M) with linear gadopentetate
dimeglumine (0.5 M) for contrast-enhanced magnetic resonance imaging (MRI) of central nervous system (CNS) lesions in Chinese
patients (N = 147) with known or suspected CNS lesions, who were enrolled in this single-blind, randomized, parallel-group study.
Three blinded independent readers evaluated all efficacy variables. The primary efficacy variable was the difference between the two
agents for the change in contrast-to-noise ratio (CNR) between non-enhanced and contrast-enhanced scans of lesions. Secondary outcomes included mean change in number of lesions detected before and after contrast enhancement, diagnostic confidence, and safety
and tolerability parameters. Gadobutrol was non-inferior to gadopentetate dimeglumine in respect to the difference in the mean change
in CNR (6.94; 95% confidence interval [CI] lower limit: −3.90; predefined maximum 95% CI lower limit: −6.52). The mean change in
the number of CNS lesions detected was greater with gadobutrol versus gadopentetate dimeglumine (1.2 vs. 0.2 lesions). Diagnostic
confidence was classified as ‘high’ for more patients with gadobutrol versus gadopentetate dimeglumine by the investigators (58.8% vs.
55.4%) and by the three blinded readers (63.6% vs. 55.7%, 23.7% vs. 18.0% and 81.7% vs. 81.0%). Both agents were well tolerated by
participating patients. We concluded that in Chinese patients with CNS lesions, gadobutrol (1.0 M) was as effective and well tolerated in
contrast-enhanced MRI as gadopentetate dimeglumine (0.5 M). Gadobutrol provided improved visualization of CNS lesions compared
with gadopentetate dimeglumine, with a comparable tolerability profile.
Keywords: gadobutrol, gadopentetate dimeglumine, CNS lesions, contrast-enhanced MRI
Magnetic Resonance Insights 2012:5 17–28
doi: 10.4137/MRI.S9348
This article is available from http://www.la-press.com.
© The author(s), publisher and licensee Libertas Academica Ltd.
This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
Magnetic Resonance Insights 2012:5
17
Liang et al
Introduction
Contrast-enhanced magnetic resonance imaging
(MRI) is the gold-standard imaging modality for the
diagnosis and treatment monitoring of central nervous
system (CNS) lesions, offering improved differential
diagnosis and grading versus non-enhanced MRI.1–3
Contrast agents such as gadopentetate dimeglumine
(Magnevist®, Bayer Schering Pharma AG, Berlin,
Germany) have been approved for CNS imaging for
over 20 years and have been administered to millions
of patients worldwide.4,5
Gadobutrol (Gadovist®, Bayer Healthcare Berlin,
Germany) is a macrocyclic, non-ionic gadoliniumbased contrast agent (GBCA) that belongs to the
same class of extracellular contrast agents as gadopentetate dimeglumine. Gadobutrol has favorable
physicochemical properties and can be formulated as
a 1.0 M solution—double the concentration of most
other GBCAs.6 The higher concentration allows a
smaller injection volume, which potentially improves
dynamic imaging, particularly in brain perfusion
imaging and in magnetic resonance angiography
(MRA).7–9 Recent comparative studies in MRA have
demonstrated higher contrast quality for gadobutrol
compared with gadopentetate dimeglumine.10–12 which
may be explained by gadobutrol’s high concentration
and relaxivity.13 Preclinical pharmacology, pharmacokinetic and toxicology studies revealed that gadobutrol is well tolerated at doses of up to 0.5 mmol/kg
body weight.14 Several Phase I–III studies have shown
a favorable safety profile for gadobutrol.15,16
Here, we report the findings of a randomized
study that compared the efficacy and safety profile
of ­gadobutrol (1.0 M) versus gadopentetate dimeglumine (0.5 M) for contrast-enhanced MRI of CNS
lesions in Chinese patients.
Materials and Methods
Study design and study population
This was a multicenter, single-blind, randomized
comparative study with independent blinded-reader
evaluation. Although on-site clinical investigators
were unblinded, all off-site readers evaluating the
image sets were blinded.
Patients were recruited from four centers in China.
Institutional ethics committee/independent review
boards at each center approved the study protocol
and informed consent forms. This study was carried
18
out in accordance with principles of the Declaration
of Helsinki (Ethical Principles for Medical Research
Involving Human Patients, revised in Edinburgh,
Scotland, October 2000). The trial was registered
with the clinical trial registry, ClinicalTrials.gov
­(Identifier: NCT00395460).
Patients aged 18–65 years with known or suspected
CNS lesions (cranial and/or spinal) requiring contrastenhanced MRI for diagnosis and treatment decision were
eligible for enrollment. All participating patients provided informed written consent. Patients were excluded
from the study if they: were pregnant or breastfeeding
females; had a known or suspected hypersensitivity
reaction to any contrast media; were contraindicated for
MRI; had received any contrast material within 24 hours
before receiving the study drugs, or were scheduled to
receive contrast material within 24 hours after study
drug administration; had severely impaired hepatic or
renal function (for example, serum glutamate pyruvate greater than two times the upper limit of reference
range or acute renal failure); had underlying diseases
or concomitant medications which may have interfered
with efficacy or safety evaluation; or were scheduled
for CNS surgery or other surgery within 24 hours after
injection with the contrast agent.
Objectives and variables
The primary objective was to evaluate the change
in contrast-to-noise ratio (CNR) in MRI between
non-enhanced and contrast-enhanced scans, and to
demonstrate non-inferiority of gadobutrol versus
gadopentetate dimeglumine for change in CNR. The
secondary objectives were to evaluate: the change in
the number of lesions detected before and after contrast enhancement; the change in diagnostic confidence; the degree of contrast enhancement for each
lesion, mainly on T1-weighted images; the change
in lesion–border delineation; and the incidence and
severity of adverse events (AEs) following injection
with gadobutrol or gadopentetate dimeglumine.
For both contrast agents, the primary variable
was evaluated for the most enhanced lesion in each
patient, and was calculated as follows:
CNR = (SI lesion − SI normal tissue)/SD background,
where ‘SI lesion’ is the signal intensity in the lesion, ‘SI
normal tissue’ is the signal intensity of the ­surrounding
Magnetic Resonance Insights 2012:5
Gadobutrol versus gadopentetate dimeglumine for enhanced MRI of CNS lesions
tissue, and ‘SD background’ is the standard deviation
of the background noise.
If two or more enhanced lesions were present, or in
case of inhomogeneous enhancement, the investigator
selected the lesion (or a part of the lesion) with maximum enhancement for measurements. The periphery
of lesions was avoided for SI measurements. The
same region of interest (ROI) was assessed for the
best pre- and post-contrast MRI scans. For measuring the signal intensity in normal tissue, the blinded
reader defined a ROI that included at least 10 pixels.
If the lesion(s) was/were smaller than 10 pixels,
no quantitative data were collected from this patient.
For normal brain tissue, the ROI was selected in the
contralateral hemisphere from the lesion and as far
away from of it as possible. In normal spine tissue,
the ROI was chosen as far as possible from the lesion.
The intensity of background noise and the standard
deviation was measured in a ROI on the same MRI
scan as the lesion but as far ventrally from the lesion
as possible.
Diagnostic confidence was defined as the degree
of confidence that the information on the images represented the true and complete clinical picture. The
investigators and the three blinded readers recorded
the degree of diagnostic confidence as ‘none’, ‘low’,
‘moderate’ or ‘high’ based on the pre- and post-­contrast
MRI scans. Border (lesion) delineation was rated on a
four-point scale (1 = none, 2 = low, 3 = moderate and
4 = high) at pre- and post-contrast MRI in both the
clinical study and in the blinded reading. The investigators and the blinded readers rated the degree of
contrast enhancement for each patient, mainly referring to T1-weighted images, on a four-point scale, as
used for border delineation.
Subgroup analyses for all efficacy variables were
performed according to type of CNS lesion. The first
subgroup included patients with primary malignant
brain tumor(s) and/or brain metastases and the second
subgroup comprised patients with other CNS lesions.
Results from the two groups were compared with
each other. Only patients who were valid for inclusion in the per-protocol set (PPS) were included in the
subgroups analyses.
Safety was evaluated by continuous monitoring
of AEs from the time of injection to 24 hours post
injection. Vital signs, physical examination and laboratory parameters (hematology, blood chemistry,
Magnetic Resonance Insights 2012:5
and ­urinalysis) were evaluated before and at 24 hours
after injection. Vital signs were also recorded immediately after the MRI examination.
Contrast administration
Patients were randomized to receive gadobutrol
(1.0 M) at a dose of 0.1 mL/kg body weight (BW;
0.1 mmol/kg BW) or gadopentetate dimeglumine
(0.5 M) at a dose of 0.2 mL/kg BW (0.1 mmol/kg
BW). The contrast agents were each administered
as a single intravenous bolus injection. Gadobutrol
was injected at a rate of 1.0 mL/s and gadopentetate
dimeglumine was injected at a rate of 2.0 mL/s. All
injections were administered with a power injector
and followed by a saline flush of 20 mL at the same
injection rate as the contrast agent.
Magnetic resonance imaging
Patients underwent MRI with a 1.5-T system (GE Medical Systems, Milwaukee, WI, USA) and a standard
head/spinal coil. A standardized MRI protocol was
used: T1- (repetition time [TR] = 200–650 ms; echo
time [TE] = 10–20 ms) and T2-weighted (TR = 1500–
2500 ms; TE = 90–120 ms) spin-echo (SE) acquisitions and fluid-attenuated inversion recovery MR
scans (TR = 6000–8000 ms; TE = 100–136 ms) of
the head before administration of the contrast agent
(slice thickness = 8 mm; matrix = 256 × 256; field
of view = 200–400 mm; inversion ­recovery = 2000;
and number of excitations [NEX] = 2). T1-weighted
SE acquisition was performed within 2–5 min of
administering the contrast agent. The same imaging system, planes of view and parameters were
used for both pre- and post-contrast examinations
in each patient, and care was taken to ensure that
image location and angulation were identical for both
­examinations. The sequence for spinal imaging comprised T1- (TR = 400–650 ms; TE = 10–20 ms) and
T2-weighted (TR = 2000–2500 ms; TE = 90–120 ms)
SE acquisitions prior to the injection of contrast agent
(slice thickness = 3 mm; matrix = 256 × 256; field of
view = 200–400 mm; and NEX = 4). All images were
handled using the Digital Imaging and Communications in Medicine format.
Image evaluation
The signal-intensity measurements for the primary
efficacy variable were performed by one independent,
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Liang et al
blinded reader at an off-site location (Reader 1). The
secondary variables were assessed by one blinded
clinical investigator at each of the four study centers
and by three independent, blinded readers (Readers 2,
3, and 4). All of the investigators and the independent readers were expert radiologists with extensive
experience in CNS imaging. The three blinded readers independently evaluated all pre- and post-contrast
images for the secondary variables including number
of lesions, contrast enhancement, border delineation,
and diagnostic confidence. Pre- and post-contrast MRI
scans were read in a randomized manner. Blinded
image evaluations were conducted using full-fidelity
digital images on Picture Archiving and Communications System (PACS), which is commonly used in
radiological practice.
Randomization and blinding
Patients were randomly assigned to receive either
gadobutrol or gadopentetate dimeglumine using a pregenerated randomization list. Patients were blinded to
ensure an adequate safety evaluation (single-blinded
design). To ensure similar proportions were included
in each study group, the non-blinded investigator carried out continuous monitoring of patients with tumor
and other lesions on-site. A blinded-reader evaluation
was performed to minimize any bias in the efficacy
assessment. Blinding of the on-site investigators was
considered to be impossible because of the different
volumes of the two contrast agents.
Statistical considerations
A sample size of 60 valid patients in each group was
considered adequate for non-inferiority testing on the
basis of a two-group, one-sided t-test with a power of
80% at a significance level of α = 5%, assuming that
the expected difference in means is 0.01 and the common standard deviation is 0.33, as shown in previous
animal and clinical studies where a standard deviation of around 0.3–0.35 has been obtained for signal
intensity measurements. Furthermore, other internal,
exploratory studies have shown that a difference of
0.01 in the CNR does not have any impact on image
quality and diagnostic performance and can be considered as non-inferior. Based on this assumption, the
sample size for each treatment group was calculated,
giving 60 patients per treatment group.
20
All patients who received contrast injection without
major protocol deviations were included in the PPS.
An intention-to-treat analysis was also carried out on
the full analysis set (FAS)—patients who received
contrast injection and had available MRI data. Safety
of the contrast agents was analyzed for all patients
who received either contrast agent.
Non-inferiority of gadobutrol versus gadopentetate dimeglumine for change in CNR was assessed
with a non-inferiority margin of 15% using a onesided, unpaired Student’s t-test, with calculation of
95% confidence intervals (CIs). Gadobutrol would
be considered to have the same efficacy compared
with gadopentetate dimeglumine if the CNR detected
in gadobutrol group was higher than 85% of that in
the gadopentetate dimeglumine group. The non­inferiority margin of 15% was chosen based on diagnostic factors, because this does not translate into
differences in enhancement that can be ­visualized.
The other efficacy variables were analyzed descriptively and the arithmetic mean of the results from
the three blinded readers was calculated where
feasible—no additional statistical comparisons were
calculated. Safety assessments of physical examinations, vital signs and laboratory data were analyzed
using descriptive statistics where appropriate. All
analyses were performed using the Statistical Analysis System (SAS® System, Release 9.1).
Results
Patient disposition
Of the 150 patients screened for the study, 147 were
randomized between April and July 2007. Of these,
72 patients received gadobutrol and 75 patients
received gadopentetate dimeglumine (Fig. 1). One
patient in the gadobutrol group withdrew consent
before the study agent was administered, and was
excluded from analyses. Another patient in the gadobutrol group did not complete the MRI examination
and no pre- and post-contrast images were ­available.
This was considered a major protocol deviation,
and the patient was excluded from the FAS and PPS
­analyses, but was included in safety analysis. All
subjects were Asian, and groups were comparable in
terms of age, sex, height, and weight (Table 1). All
pregnancy tests performed on women of childbearing
age were negative.
Magnetic Resonance Insights 2012:5
Gadobutrol versus gadopentetate dimeglumine for enhanced MRI of CNS lesions
Approximately one-third of the patients in each
treatment group had malignant, primary brain
tumor(s) and/or brain metastases (21 patients
in the gadobutrol group and 25 in the gadopentetate ­dimeglumine group) and over two-thirds of
the patients had other CNS lesions (49 receiving
gadobutrol and 50 receiving gadopentetate
­dimeglumine). The other most frequently identified
CNS lesions included meningioma (gadobutrol,
n = 20; gadopentetate dimeglumine, n = 21),
pituitary adenoma ­(gadobutrol, n = 3; gadopentetate dimeglumine, n = 5), cerebral infarction (gadobutrol, n = 3; gadopentetate dimeglumine, n = 1),
cavernous hemangioma (gadobutrol, n = 4; gadopentetate dimeglumine, n = 0) and brain cysticercosis (gadobutrol, n = 3; gadopentetate dimeglumine,
n = 0).
Contrast-to-noise ratio
The mean change in the CNR (post- versus precontrast MRI) was higher with gadobutrol (50.41)
than with gadopentetate dimeglumine (43.47; PPS;
Table 2). The mean difference in CNR between gadobutrol and gadopentetate dimeglumine was 6.94.
The lower limit of the 95% CI was −3.90, confirming non-inferiority of gadobutrol versus gadopentetate dimeglumine because the lower limit of the
95% CI was to the right side of −∆ = −15% (ie,
−6.52). The PPS and FAS included the same patients
in each treatment group and, therefore, had identical
results.
For the subgroup analysis for patients with brain
tumor(s)/metastases or other CNS lesions, the mean
change in CNR was generally higher in patients
with brain tumor(s)/metastases than in patients
with other types of CNS lesions. For patients with
brain tumor(s)/metastases, the mean change in CNR
(SD) was 54.95 (42.41) for gadobutrol versus 46.56
(30.07) for gadopentetate dimeglumine. For patients
with other types of CNS lesions, the mean change
in CNR was 48.51 (36.99) for gadobutrol versus
41.86 (43.38) for gadopentetate dimeglumine. The
mean difference between gadobutrol and gadopentetate dimeglumine for the intra-individual change
in CNR was higher in patients with brain tumor(s)/­
metastases (8.39) than in patients with other CNS
lesions (6.66).
Magnetic Resonance Insights 2012:5
Number of subjects
screened (n = 150)
Number of subjects
randomized (n = 147)
Randomized to
gadopentetate
dimeglumine (n = 75)
Completed the
study (n = 75)
Screening failures
Withdrawal of consent (n = 2)
Poor physical condition (n = 1)
Randomized to
gadobutrol (n = 72)
Completed the
study (n = 71)
Withdrew consent
before study agent
injection (n = 1)
Figure 1. Patient disposition.
Change in the number of lesions
detected by contrast-enhanced scan
Both contrast agents increased the mean number of
lesions detected in post-contrast MRI relative to precontrast MRI, as evaluated by the investigators and the
blinded readers, but more lesions were detected with
gadobutrol than with gadopentetate dimeglumine. For
the investigator evaluations, the mean number of lesions
increased from 3.3 pre-contrast to 4.0 post-contrast in
the gadobutrol group and from 1.8 to 1.9 lesions in the
gadopentetate dimeglumine group. The same trend was
observed for each of the readers and for the average of
all three readers (Table 3). Overall, gadobutrol consistently showed a higher mean change in the number of
detected lesions than gadopentetate dimeglumine.
In the subgroup analysis of patients with brain
tumor(s)/metastases, the mean number of detected
lesions increased from pre- to post-contrast MRI, as
determined by the investigators and all three blinded
readers for both treatment groups. Similar findings
were obtained in patients with other CNS lesions,
except for investigator-determined lesions in the
gadopentetate dimeglumine group, as the mean number of detected lesions remained the same at pre- and
post-contrast MRI in this group (Table 4).
Change in diagnostic confidence
In comparison with pre-contrast MRI with mainly ‘moderate’ ratings, diagnostic confidence was ­predominantly
rated as ‘improved’at post-contrast MRI in both treatment
groups. The number of patients with ‘improved’ diagnostic confidence ratings was higher after gadobutrol
administration versus gadopentetate ­dimeglumine
21
Liang et al
Table 1. Patient characteristics.
Gadobutrol
(n = 71)
Age (years)
42.8 (12.24)
Male, n (%)
38 (53.5)
Female, n (%)
33 (46.5)
Weight (kg)
63.64 (10.99)
Height (cm)
164.84 (7.61)
Indication for contrast enhancement MRI procedure, n (%)
Primary malignant brain tumor(s)
21 (29.6)
and/or brain metastasis
Other CNS lesions
50 (70.4)
Gadopentetate
dimeglumine (n = 75)
Overall
(n = 146)
43.9 (10.10)
33 (44.0)
42 (56.0)
64.49 (12.47)
165.01 (8.39)
43.4 (11.17)
71 (48.6)
75 (51.4)
64.08 (11.74)
164.92 (7.99)
25 (33.3)
46 (31.5)
50 (66.7)
100 (68.5)
Note: Results are means (standard deviation) or n (%).
Abbreviations: MRI, magnetic resonance imaging; CNS, central nervous system.
for the investigators (97.1% vs. 86.7%) and for two of
the three blinded readers (Reader 3: 84.3% vs. 81.3%;
Reader 4: 85.7% vs. 84.0%). Reader 2 rated more
patients with ‘improved’ diagnostic confidence after
gadopentetate dimeglumine administration (81.3%)
than with gadobutrol (78.6%).
Improved diagnostic confidence was further ­classified
as ‘excellent’ in a higher number of patients after gadobutrol administration versus ­gadopentetate dimeglumine (investigators: 58.8% vs. 55.4%; Reader 2: 63.6%
vs. 55.7%; Reader 3: 23.7% vs. 18.0%; Reader 4: 81.7%
vs. 81.0%).
Table 2. Mean change in contrast-to-noise ratio—
per-protocol set.
Mean pre-contrast
CNR
Mean post-contrast
CNR
Change in mean
CNR
Lower limit of 95%
CI for change in
mean CNR
Difference
(gadobutrol–
gadopentetate
dimeglumine)
Gadobutrol
(n = 68)
Gadopentetate
dimeglumine
(n = 73)
-5.89 (23.82)
-9.43 (16.43)
44.51 (38.38)
34.04 (35.45)
50.41 (38.45)
43.47 (39.18)
42.63
35.83
Mean = 6.94
Lower limit of 95% CI = -3.90
Note: Results are means (standard deviation).
Abbreviations: CNR, contrast-to-noise ratio; CI, confidence interval.
22
In the subgroup analysis, the proportion of patients
with ‘improved’ diagnostic confidence ratings after
gadobutrol administration was generally higher in
patients with brain tumor(s)/metastases than those
with other CNS lesions (investigators: 95.2% vs.
98.0%; Reader 2: 85.7% vs. 75.5%; Reader 3: 95.2%
vs. 79.6%; Reader 4: 95.2% vs. 81.6%). A higher
proportion of patients had ‘improved’ ratings with
gadobutrol versus gadopentetate dimeglumine for the
investigator and two of the blinded readers in patients
with brain tumor(s)/­metastases (investigators: 95.2%
vs. 92.0%; Reader 2: 85.7% vs. 88.0%; Reader 3:
95.2% vs. 88.0%; Reader 4: 95.2% vs. 92.0%) and
CNS lesions (investigators: 98.0% vs. 84.0%; Reader
2: 75.5% vs. 78.0%; Reader 3: 79.6% vs. 78.0%;
Reader 4: 81.6% vs. 80.0%).
Lesion contrast enhancement
Lesion contrast enhancement was reported as ‘no’ for
the investigators and the blinded readers for all patients
at pre-contrast MRI. At post-contrast MRI, the degree
of lesion contrast enhancement shifted to ‘excellent’
for most of the patients, as reported by the investigator
and two of the three blinded readers. There were more
patients with ‘excellent’ ratings with gadobutrol versus gadopentetate dimeglumine (investigator: 54.3%
vs. 46.7%; Reader 2: 57.1% vs. 52.0%; Reader 3:
21.4% vs. 9.3%; Reader 4: 52.9% vs. 49.3%).
Similarly, the mean change in lesion contrast
enhancement from pre- to post-contrast MRI was
consistently higher with gadobutrol versus gadopentetate dimeglumine (Table 5).
Magnetic Resonance Insights 2012:5
Gadobutrol versus gadopentetate dimeglumine for enhanced MRI of CNS lesions
Table 3. Mean number of detected lesions at pre- and post-contrast MRI and change in mean number (post-contrast minus
pre-contrast) by treatment—per-protocol set.
Time
Treatment
Mean number of detected lesions
Average reader
Pre
Gadobutrol
Gadopentetate dimeglumine
Post
Gadobutrol
Gadopentetate dimeglumine
Mean change in number of detected lesions
Average reader
Gadobutrol
Gadopentetate dimeglumine
n
Mean
SD
Min
Max
70
75
70
75
3.1
3.1
4.3
3.3
8.52
17.75
13.58
19.31
0
0
0
0
52
155
100
167
70
75
1.2
0.2
6.06
1.4
-3
0
48
12
Note: Average reader, mean of blinded reader assessment.
Abbreviation: SD, standard deviation.
Table 4. Change in mean number of detected lesions (post-contrast minus pre-contrast) by treatment—per-protocol set,
subgroup analysis.
Treatment
n
Mean
Patients with primary malignant brain tumor(s)/brain metastasis
Investigator
Gadobutrol
21
0.7
Gadopentetate dimeglumine
25
0.4
Reader 2
Gadobutrol
21
0.4
Gadopentetate dimeglumine
25
0.2
Reader 3
Gadobutrol
21
0.5
Gadopentetate dimeglumine
25
0.2
Reader 4
Gadobutrol
21
0.1
Dimeglumine
25
0.0
Average reader
Gadobutrol
21
0.3
Gadopentetate dimeglumine
25
0.1
Patients with other CNS lesions
Investigator
Gadobutrol
49
0.7
Gadopentetate dimeglumine
50
0.0
Reader 2
Gadobutrol
49
1.8
Gadopentetate dimeglumine
50
0.3
Reader 3
Gadobutrol
49
2.2
Gadopentetate dimeglumine
50
0.3
Reader 4
Gadobutrol
49
0.7
Gadopentetate dimeglumine
50
0.2
Average reader
Gadobutrol
49
1.6
Gadopentetate dimeglumine
50
0.3
SD
Min
Max
2.61
1.41
0
0
12
7
1.75
0.55
0
0
8
2
2.18
0.72
0
0
10
3
0.30
0.20
0
0
1
1
1.38
0.35
0
0
6
1
2.57
0.00
0
0
16
0
8.20
2.26
0
0
56
16
11.53
1.70
0
0
79
12
3.24
1.13
-8
0
16
8
7.18
1.70
-3
0
48
12
Note: Average reader, mean of blinded reader assessment.
Abbreviations: SD, standard deviation; CNS, central nervous system.
Magnetic Resonance Insights 2012:5
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Liang et al
Change in border (lesion) delineation
Discussion
Safety and tolerability
Contrast-to-noise ratio
Border delineation shifted from mainly ‘moderate’
at pre-contrast MRI to ‘excellent’ in the majority
of patients at post-contrast MRI, as assessed by the
investigator and by two of the three blinded readers
in both treatment groups. The proportions of patients
with excellent ratings were higher with gadobutrol
versus gadopentetate dimeglumine (investigator:
58.6% vs. 53.3%; Reader 2: 61.4% vs. 57.3%; Reader
3: 28.6% vs. 14.7%; Reader 4: 54.3% vs. 56.0%).
The findings were similar for the mean values in
border delineation based on scores (where 1 = ‘no’
and 4 = ‘excellent’). The mean change in border
delineation from pre- to post-contrast MRI was
consistently higher with gadobutrol versus gadopentetate dimeglumine (investigators: 1.1 vs. 1.0;
Reader 2: 1.4 vs. 1.3; Reader 3: 0.9 vs. 0.8; Reader 4:
1.0 vs. 0.9).
In the subgroup analysis, two of the three blinded
readers assessed border delineation as ‘excellent’
after gadopentetate dimeglumine administration,
and ‘good’ after gadobutrol in patients with brain
tumor(s)/metastases. In patients with other CNS, two
of the three blinded readers assessed ‘excellent’ border
delineation lesions for both agents. The mean values
in lesion delineation showed an increase at postcontrast MRI in both patient subgroups with slightly
higher mean scores after gadobutrol compared with
gadopentetate dimeglumine.
The safety analysis population comprised 146
patients (gadobutrol: n = 71; gadopentetate dimeglumine: n = 75). Overall, six (4.1%) patients reported
eight AEs following contrast agent administration
(gadobutrol: n = 2 [2.8%]; four AEs); gadopentetate
dimeglumine: n = 4 [5.3%]; four AEs; Table 6). All
AEs were evaluated as being mild in intensity by the
investigators. One AE in each group was considered
possibly related to the respective contrast agent (gadobutrol: insomnia; gadopentetate dimeglumine: erythema), all other AEs were considered ‘unrelated’ to
treatment by the investigators. All documented AEs
had resolved at the conclusion of the study. No significant changes in vital signs, laboratory parameters
or physical examination findings occurred following
the administration of either contrast agent.
24
Extracellular GBCAs, such as gadopentetate dimeglumine, have been used successfully for over 20 years in
contrast-enhanced MRI of the CNS. Gadobutrol is currently the only GBCA available at 1.0 M ­concentration.
It has been shown to have a high relaxivity and a compact bolus profile and, thus, is considered to be promising in the field of CNS imaging.2
The goal of our study was to demonstrate that in
a Chinese patient population gadobutrol has similar
efficacy to gadopentetate dimeglumine, a well-established GBCA, to obtain marketing approval in China.
This study used a non-inferiority approach to compare gadobutrol 1.0 M with gadopentetate dimeglumine 0.5 M for the mean change in CNR between
measurements pre- and post-contrast-enhanced MRI.
This technical parameter enables a good estimate of
the performance of a contrast agent in terms of visualization of enhanced lesions and delineation of the
lesion borders. The evaluation of border delineation
and degree of contrast enhancement, which are also
used in clinical practice and contribute to radiological diagnoses, gave supportive evidence. In addition
to the investigators’ assessments, a prospectively
planned independent blinded-reader evaluation of
the image data sets was carried out by certified radiologists who were not involved in the clinical study
and were experienced in the evaluation of MRI CNS
images.
The primary efficacy variable in this study was the
change in CNR in post-contrast MRI images compared with pre-contrast images of CNS lesions.
A greater change was observed with gadobutrol
compared with gadopentetate dimeglumine on conventional T1-weighted imaging. The distribution of
primary malignant brain tumor(s)/metastases and
other CNS lesions was similar between the treatment
groups. Therefore, the higher CNR can be regarded
as a positive effect of gadobutrol. Indeed, in both
subgroups evaluated here (ie, patients with brain
tumor(s)/metastases and patients with other CNS
lesions), the mean change in CNR was higher with
gadobutrol than with gadopentetate dimeglumine.
Overall, these results support those of Attenberger
et al, who showed superior improvement in CNR
Magnetic Resonance Insights 2012:5
Gadobutrol versus gadopentetate dimeglumine for enhanced MRI of CNS lesions
Table 5. Enhancement change between pre- and post-contrast MRI—per-protocol set, subgroup analysis.
Treatment
n
Mean
Patients with primary malignant brain tumor(s)/brain metastasis
Investigator
Gadobutrol
21
2.3
Gadopentetate dimeglumine
25
2.4
Reader 2
Gadobutrol
21
2.2
Gadopentetate dimeglumine
25
2.0
Reader 3
Gadobutrol
21
1.9
Gadopentetate dimeglumine
25
1.6
Reader 4
Gadobutrol
21
2.2
Gadopentetate dimeglumine
25
2.2
Average reader
Gadobutrol
21
2.1
Gadopentetate dimeglumine
25
1.9
Patients with other CNS lesions
Investigator
Gadobutrol
49*
2.4
Gadopentetate dimeglumine
50
2.2
Reader 2
Gadobutrol
49
2.0
Gadopentetate dimeglumine
50
2.0
Reader 3
Gadobutrol
49
1.7
Gadopentetate dimeglumine
50
1.6
Reader 4
Gadobutrol
49
2.2
Gadopentetate dimeglumine
50
2.0
Average reader
Gadobutrol
49
1.9
Gadopentetate dimeglumine
50
1.9
SD
Min
Max
0.97
0.76
1
0
3
3
1.12
1.03
0
0
3
3
0.79
0.71
0
0
3
3
0.89
0.91
0
0
3
3
0.83
0.81
0
0
3
3
0.84
0.92
0
0
3
3
1.29
1.29
0
0
3
3
1.05
0.97
0
0
3
3
1.12
1.18
0
0
3
3
1.09
1.06
0
0
3
3
Notes: *One reading was missing in the gadobutrol group. Average reader, mean of blinded reader assessment.
Abbreviations: SD, standard deviation; CNS, central nervous system.
Table 6. Adverse events reported during the study.
Patient ID*
Number of AEs
experienced by patient
AE
Intensity
Relationship to study drug as
rated by the center investigators
Gadobutrol
A
2
B
2
Insomnia
Nausea
Serum glutamic oxaloacetic
transferase increased
Serum glutamic pyruvic
transaminase increased
Mild
Mild
Mild
Possible
Unrelated
Unlikely
Mild
Unlikely
Hyponatremia
Erythema
Feeling abnormal
Insomnia
Mild
Mild
Mild
Mild
Unrelated
Possible
Unlikely
Unrelated
Gadopentetate dimeglumine
C
1
D
1
E
1
F
1
Notes: *Patients assigned arbitrary identification for the purpose of the table. Two patients receiving gadobutrol experienced two adverse events each;
four patients receiving gadopentetate dimeglumine experienced one adverse event.
Abbreviations: ID, arbitrary patient identification; AE, adverse event.
Magnetic Resonance Insights 2012:5
25
Liang et al
with gadobutrol versus gadopentetate dimeglumine
in a rat brain tumor model.17
Lesion detection
In our study, both contrast agents increased the number of lesions detected. However, the mean change
in the number of detected lesions was consistently
higher with gadobutrol than with gadopentetate
dimeglumine as assessed by the investigator and
the blinded readers. This was also confirmed in the
subgroup analysis. The greater number of lesions
detected using gadobutrol may be attributed to its high
T1- and T2-weighted relaxivity compared with gadopentetate dimeglumine, which contributes not only to
improved enhanced image contrast, but also proves
advantageous in terms of image quality and diagnostic confidence.18 The clinical information concerning
additional lesions is particularly important in patients
with brain metastases and for patients with multiple
sclerosis in terms of treatment planning and evaluating prognosis.
The detection of lesions depends mainly on the
contrast of the lesion versus background noise, on
lesion size and lesion location. Further increasing contrast by injecting a paramagnetic contrast
agent should improve conspicuity and detectability of lesions, as has been demonstrated for gadopentetate dimeglumine through many years of
clinical experience.18–21 In addition, the presence or
absence of an enhancing lesion contributes greatly
to the differential diagnosis in clinical settings. The
results of this study indicate that gadobutrol has
at least a similar efficacy to gadopentetate dimeglumine, supporting the results of previous studies
by Anzalone et al and Kim et al, in which gadobutrol-enhanced imaging enabled the detection
of additional lesions that were not detected using
gadopentetate dimeglumine.12,22
The study by Anzalone et al was similar to this
one, comparing the effects of standard doses of
gadobutrol and gadopentetate dimeglumine in
patients with at least one cerebral metastasis and
it also ­demonstrated significant advantages with
­gadobutrol.22 At equal gadolinium dose, better
visualization of brain metastasis with gadobutrol
compared with gadopentetate dimeglumine was
demonstrated, and gadobutrol improved the conspicuity of detected lesions.22
26
Both contrast agents improved lesion delineation
versus pre-contrast images; however, gadobutrol
improved lesion delineation to a greater extent than
did gadopentetate dimeglumine. The improved lesion
detection and border delineation based on the contrast
enhancement following gadobutrol administration
suggests that this compound could exclude further
CNS lesions, and increase the radiologists’ confidence
in interpreting the images. Our results also support the
findings of Giesel et al who concluded that the higher
concentration of gadobutrol (1.0 M) offers advantages
over the standard concentration of 0.5 M gadopentetate dimeglumine in terms of lesion delineation.23
As would be expected, compared with pre-contrast imaging, the mean number of lesions detected
on post-contrast images increased with both contrast agents in these patients with CNS lesions. The
increase in number of lesions detected was greater
with gadobutrol compared with gadopentetate dimeglumine, a finding that was also demonstrated in
both subgroups of patients, namely those with brain
tumor(s)/metastases and those with other CNS lesions.
­However, the mean number of detected lesions was
lower at pre- and post-contrast MRI in patients with
brain tumor(s)/metastases, compared with the whole
group. This difference probably reflected the nature
of primary malignant brain tumors, which were the
most common malignant lesions in this study. Indeed,
most patients had a primary malignant tumor, which
is usually unifocal. As a result, one would expect the
number of lesions detected in these subgroups to be
less than that in other subgroups, independent of the
contrast agent used.
Diagnostic confidence
The improvement in CNR and other lesion
visualization parameters using gadobutrol 1.0 M also
translated into improvements in diagnostic confidence,
which is an important factor in terms of further
patient ­management. Low diagnostic confidence may
necessitate additional diagnostic procedures. In this
study, both contrast agents improved the ­radiologist’s
­diagnostic confidence compared with pre-contrast
imaging, supporting results from previous studies.2,23
Safety and tolerability
All of the AEs noted in this study are well known for
gadolinium-containing contrast agents and all were
Magnetic Resonance Insights 2012:5
Gadobutrol versus gadopentetate dimeglumine for enhanced MRI of CNS lesions
of mild intensity and mostly of short duration. No significant differences in safety variables assessed were
observed between the two contrast agents. Thus, the
safety profiles of gadobutrol and gadopentetate dimeglumine were both excellent and consistent with findings from previous clinical studies and post-­marketing
surveillance reports.10,24–26
Limitations
As a single-blinded, non-inferiority approach was
used in this study, this limits the study results with
regard to the comparison of gadobutrol and gadopentetate dimeglumine. However, it should be noted
that all off-site readers were blinded. Apart from
the primary efficacy endpoint, no formal statistical
comparisons were made. Potential differences with
regard to imaging properties cannot be detected or
assessed with this study design. Intra-individual
comparison trials would be necessary to investigate
this further. It would be useful if such trials included
analyses of brain tumor/metastases and meningioma
subgroups.
This study did not assess whether contrast
enhancement (using either gadobutrol or gadopentetate dimeglumine) would translate into better treatment decisions. It is likely that the higher CNR, and
diagnostic confidence, in particular the improved
border delineation of lesions observed with gadobutrol, would translate into better understanding of
the extent of the tumor and thus aid surgical management and provide therapeutic benefits. Furthermore,
this study used an imaging protocol which is standard
in clinical practice for CNS imaging. The behavior
of the two contrast agents during the dynamic phase
of contrast-enhanced imaging was not assessed using
this protocol, which is important when in assessing
the properties of vascularity and may help to differentiate lesion types, as shown in Mangla et al 2011,
which was not available at the time that the study was
conducted.27
Conclusion
The clinical results of this study in Chinese patients
indicate that gadobutrol 1.0 M is a safe and efficacious
MRI agent, supporting previously reported data.
We also found that gadobutrol was comparable to
gadopentetate dimeglumine in terms of safety and
tolerability.
Magnetic Resonance Insights 2012:5
Abbreviations Used
MRI, magnetic resonance imaging; CNS, central nervous system; CNR, contrast-to-noise ratio; GBCA,
gadolinium-based contrast agent; MRA, magnetic
resonance angiography; AE, adverse events; ROI,
region of interest; PPS, per-protocol set; TR, repetition time; TE, echo time; SE, spin-echo; NEX, number
of excitations; FAS, full-analysis set; CI, confidence
intervals; SD, standard deviation.
Author Contributions
Conceived and designed the experiments: JB, XF,
LM, DW, YH. Analysed the data: JY, ZY, SC, HH,
XF, JB. Wrote the first draft of the manuscript: XF,
LM, DW, YH, ZL. Contributed to the writing of the
manuscript: JB, PL. Agree with manuscript results
and conclusions: ZL, LM, DW, YH, PL, JY, ZY, SC,
HH, JB, XF. Jointly developed the structure and arguments for the paper: ZL, LM, DW, YH, PL, JY, ZY,
SC, HH, JB, XF. Made critical revisions and approved
final version: ZL, LM, DW, YH, PL, JY, ZY, SC, HH,
JB, XF. All authors reviewed and approved of the
final manuscript.
Funding
This project was supported by “The major research
and development project of innovative drugs, ­Ministry
of Science and Technology” (2008ZX09312-010),
China. Editorial support was provided by Fiona
­Murray-Zmijewski, Medicus International, and
funded by Bayer Schering Pharma AG.
Competing Interests
Dr. Ping Li is a full-time employee of Bayer Healthcare
Company Ltd., Beijing. Dr. Josy Breuer is a full-time
employee of Bayer Schering Pharma AG, Berlin. The
remaining authors have no conflict of interest to declare.
Disclosures and Ethics
As a requirement of publication author(s) have
provided to the publisher signed confirmation
of compliance with legal and ethical obligations
including but not limited to the following: authorship
and contributorship, conflicts of interest, privacy and
confidentiality and (where applicable) protection of
human and animal research subjects. The authors
have read and confirmed their agreement with the
ICMJE authorship and conflict of interest criteria.
27
Liang et al
The authors have also confirmed that this article is
unique and not under consideration or published in
any other publication, and that they have permission
from rights holders to reproduce any copyrighted
material. Any disclosures are made in this section.
The external blind peer reviewers report no conflicts
of interest.
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