Efficacy and Safety of Gadobutrol (1.0 M) versus Gadopentetate Dimeglumine (.5 M) for Enhanced Mri of Cns Lesions: A Phase Iii,Multicenter,Single-blind,Randomized Study in Chinese Patients

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

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 gadolinium-based 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 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 contrast-enhanced 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) / S D background,

where ‘SI lesion’ is the signal intensity in the lesion, ‘SI normal tissue’ is the signal intensity of the surrounding 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, 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, 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.

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 one-sided, 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 non-inferiority 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.

Table 1

Patient characteristics.

	Gadobutrol (n = 71)	Gadopentetate dimeglumine (n = 75)	Overall (n = 146)
Age (years)	42.8 (12.24)	43.9 (10.10)	43.4 (11.17)
Male, n (%)	38 (53.5)	33 (44.0)	71 (48.6)
Female, n (%)	33 (46.5)	42 (56.0)	75 (51.4)
Weight (kg)	63.64 (10.99)	64.49 (12.47)	64.08 (11.74)
Height (cm)	164.84 (7.61)	165.01 (8.39)	164.92 (7.99)
Indication for contrast enhancement MRI procedure, n (%)
Primary malignant brain tumor(s) and/or brain metastasis	21 (29.6)	25 (33.3)	46 (31.5)
Other CNS lesions	50 (70.4)	50 (66.7)	100 (68.5)

Note: Results are means (standard deviation) or n (%).

Abbreviations: MRI, magnetic resonance imaging; CNS, central nervous system.

Figure 1

Patient disposition.

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 pre-contrast 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 -Δ = -15% (ie, -6.52). The PPS and FAS included the same patients in each treatment group and, therefore, had identical results.

Table 2

Mean change in contrast-to-noise ratio— per-protocol set.

	Gadobutrol (n = 68)	Gadopentetate dimeglumine (n = 73)
Mean pre-contrast CNR	-5.89 (23.82)	-9.43 (16.43)
Mean post-contrast CNR	44.51 (38.38)	34.04 (35.45)
Change in mean CNR	50.41 (38.45)	43.47 (39.18)
Lower limit of 95% CI for change in mean CNR	42.63	35.83
Difference (gadobutrol–gadopentetate dimeglumine)	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.

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).

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 pre-contrast 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.

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	n	Mean	SD	Min	Max
Mean number of detected lesions
Average reader
Pre	Gadobutrol	70	3.1	8.52	0	52
	Gadopentetate dimeglumine	75	3.1	17.75	0	155
Post	Gadobutrol	70	4.3	13.58	0	100
	Gadopentetate dimeglumine	75	3.3	19.31	0	167
Mean change in number of detected lesions
Average reader	Gadobutrol	70	1.2	6.06	-3	48
	Gadopentetate dimeglumine	75	0.2	1.4	0	12

Note: Average reader, mean of blinded reader assessment.

Abbreviation: SD, standard deviation.

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).

Table 4

Change in mean number of detected lesions (post-contrast minus pre-contrast) by treatment—per-protocol set, subgroup analysis.

Treatment	n	Mean	SD	Min	Max
Patients with primary malignant brain tumor(s)/brain metastasis
Investigator
Gadobutrol	21	0.7	2.61	0	12
Gadopentetate dimeglumine	25	0.4	1.41	0	7
Reader 2
Gadobutrol	21	0.4	1.75	0	8
Gadopentetate dimeglumine	25	0.2	0.55	0	2
Reader 3
Gadobutrol	21	0.5	2.18	0	10
Gadopentetate dimeglumine	25	0.2	0.72	0	3
Reader 4
Gadobutrol	21	0.1	0.30	0	1
Dimeglumine	25	0.0	0.20	0	1
Average reader
Gadobutrol	21	0.3	1.38	0	6
Gadopentetate dimeglumine	25	0.1	0.35	0	1
Patients with other CNS lesions
Investigator
Gadobutrol	49	0.7	2.57	0	16
Gadopentetate dimeglumine	50	0.0	0.00	0	0
Reader 2
Gadobutrol	49	1.8	8.20	0	56
Gadopentetate dimeglumine	50	0.3	2.26	0	16
Reader 3
Gadobutrol	49	2.2	11.53	0	79
Gadopentetate dimeglumine	50	0.3	1.70	0	12
Reader 4
Gadobutrol	49	0.7	3.24	-8	16
Gadopentetate dimeglumine	50	0.2	1.13	0	8
Average reader
Gadobutrol	49	1.6	7.18	-3	48
Gadopentetate dimeglumine	50	0.3	1.70	0	12

Note: Average reader, mean of blinded reader assessment.

Abbreviations: SD, standard deviation; CNS, central nervous system.

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 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%).

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).

Table 5

Enhancement change between pre- and post-contrast MRI—per-protocol set, subgroup analysis.

Treatment	n	Mean	SD	Min	Max
Patients with primary malignant brain tumor(s)/brain metastasis
Investigator
Gadobutrol	21	2.3	0.97	1	3
Gadopentetate dimeglumine	25	2.4	0.76	0	3
Reader 2
Gadobutrol	21	2.2	1.12	0	3
Gadopentetate dimeglumine	25	2.0	1.03	0	3
Reader 3
Gadobutrol	21	1.9	0.79	0	3
Gadopentetate dimeglumine	25	1.6	0.71	0	3
Reader 4
Gadobutrol	21	2.2	0.89	0	3
Gadopentetate dimeglumine	25	2.2	0.91	0	3
Average reader
Gadobutrol	21	2.1	0.83	0	3
Gadopentetate dimeglumine	25	1.9	0.81	0	3
Patients with other CNS lesions
Investigator
Gadobutrol	49^*	2.4	0.84	0	3
Gadopentetate dimeglumine	50	2.2	0.92	0	3
Reader 2
Gadobutrol	49	2.0	1.29	0	3
Gadopentetate dimeglumine	50	2.0	1.29	0	3
Reader 3
Gadobutrol	49	1.7	1.05	0	3
Gadopentetate dimeglumine	50	1.6	0.97	0	3
Reader 4
Gadobutrol	49	2.2	1.12	0	3
Gadopentetate dimeglumine	50	2.0	1.18	0	3
Average reader
Gadobutrol	49	1.9	1.09	0	3
Gadopentetate dimeglumine	50	1.9	1.06	0	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.

Change in border (lesion) delineation

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 post-contrast MRI in both patient subgroups with slightly higher mean scores after gadobutrol compared with gadopentetate dimeglumine.

Safety and tolerability

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.

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	Insomnia	Mild	Possible
		Nausea	Mild	Unrelated
B	2	Serum glutamic oxaloacetic transferase increased	Mild	Unlikely
		Serum glutamic pyruvic transaminase increased	Mild	Unlikely
Gadopentetate dimeglumine
C	1	Hyponatremia	Mild	Unrelated
D	1	Erythema	Mild	Possible
E	1	Feeling abnormal	Mild	Unlikely
F	1	Insomnia	Mild	Unrelated

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.

Discussion

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.

Contrast-to-noise ratio

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 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

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 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.

Abbreviations Used

MRI

magnetic resonance imaging

CNS

central nervous system

CNR

contrast-to-noise ratio

GBCA

gadolinium-based contrast agent

MRA

magnetic resonance angiography

adverse events

ROI

region of interest

PPS

per-protocol set

repetition time

echo time

spin-echo

NEX

number of excitations

FAS

full-analysis set

confidence intervals

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.

Footnotes

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. 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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