NCT01344447: GEMSAV

Gadobutrol Enhanced MRA of the Supra-aortic Vessels

Completed Phase 3 Results posted Last updated 4 January 2019

What this trial tests

Phase 3 trial testing Gadobutrol (Gadovist, BAY86-4875) in Carotid Stenosis in 479 participants. Completed in 28 May 2014.

Timeline

12 May 2011

Primary endpoint
28 May 2014

28 May 2014

Quick facts

Lead sponsor	Bayer
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	diagnostic
Enrollment	479
Start date	12 May 2011
Primary completion	28 May 2014
Estimated completion	28 May 2014
Sites	56 locations across France, Italy, Austria, Sweden, Germany, Poland, South Korea, Argentina

Drugs / interventions tested

• Gadobutrol (Gadovist, BAY86-4875) — full drug profile →

Conditions studied

• Carotid Stenosis — all drugs for Carotid Stenosis →

Sponsor

Bayer — full company profile →

Who can join

18 and older, any sex, with Carotid Stenosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA Primary · Images were taken pre-injection and post-injection

Each vascular segment was visualized using unenhanced MRA and gadobutrol-enhanced MRA, characterized by the on-site investigators, three independent blinded readers (BR) (BR 1, BR 2 and BR 3) and majority readers (the outcome determined by at least two of the blinded readers). A segment was assessable if it was visualized along its entire length and if any region of stenosis, was measured reliably. There were 21 segments of the supra-aortic arteries assessed per participant.

Majority reader

Group	Value	95% CI
Gadobutrol-enhanced MRA	95.0
Unenhanced MRA	72.7

Blinded reader 1

Group	Value	95% CI
Gadobutrol-enhanced MRA	88.2
Unenhanced MRA	24.4

Blinded reader 2

Group	Value	95% CI
Gadobutrol-enhanced MRA	94.9
Unenhanced MRA	75.3

Blinded reader 3

Group	Value	95% CI
Gadobutrol-enhanced MRA	97.4
Unenhanced MRA	82.4

Clinical investigators

Group	Value	95% CI
Gadobutrol-enhanced MRA	97.0
Unenhanced MRA	78.6

Sensitivity for Detection of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA Primary · Images were taken pre-injection and post-injection

Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the standard of reference (SoR) (computed tomographic angiography \[CTA\]; blinded readers). This was determined using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded.

Majority reader (n=141/158)

Group	Value	95% CI
Gadobutrol-enhanced MRA	60.1
Non-contrast MRA	54.4

Blinded reader 1 (n=141/158)

Group	Value	95% CI
Gadobutrol-enhanced MRA	59.5
Non-contrast MRA	54.4

Blinded reader 2 (n=141/158)

Group	Value	95% CI
Gadobutrol-enhanced MRA	59.5
Non-contrast MRA	54.1

Blinded reader 3 (n=141/158)

Group	Value	95% CI
Gadobutrol-enhanced MRA	58.2
Non-contrast MRA	55.7

Clinical investigators (n=238/297)

Group	Value	95% CI
Gadobutrol-enhanced MRA	60.9
Non-contrast MRA	39.4

Specificity for Exclusion of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA Primary · Images were taken pre-injection and post-injection

Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the SoR (CTA; blinded readers). This was determined using the NASCET criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded.

Majority reader (n=457/9321)

Group	Value	95% CI
Gadobutrol-enhanced MRA	96.1
Non-contrast MRA	87.3

Blinded reader 1 (n=457/9321)

Group	Value	95% CI
Gadobutrol-enhanced MRA	92.0
Non-contrast MRA	61.7

Blinded reader 2 (n=457/9321)

Group	Value	95% CI
Gadobutrol-enhanced MRA	94.7
Non-contrast MRA	85.1

Blinded reader 3 (n=457/9321)

Group	Value	95% CI
Gadobutrol-enhanced MRA	96.7
Non-contrast MRA	89.1

Clinical investigators (n=457/9133)

Group	Value	95% CI
Gadobutrol-enhanced MRA	98.1
Non-contrast MRA	89.1

Minimum Gadobutrol Performance for Sensitivity: Sensitivity > 50% Primary · Images were taken pre-injection and post-injection

Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter.

Majority reader (n=135/149)

Group	Value	95% CI
Gadobutrol-enhanced MRA	61.7

Blinded reader 1 (n=132/146)

Group	Value	95% CI
Gadobutrol-enhanced MRA	60.3

Blinded reader 2 (n=139/156)

Group	Value	95% CI
Gadobutrol-enhanced MRA	59.6

Blinded reader 3 (n=140/155)

Group	Value	95% CI
Gadobutrol-enhanced MRA	58.7

Clinical investigators (n=230/283)

Group	Value	95% CI
Gadobutrol-enhanced MRA	61.5

Minimum Gadobutrol Performance for Specificity: Specificity > 50% Primary · Images were taken pre-injection and post-injection

Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter.

Majority reader (n=457/8805)

Group	Value	95% CI
Gadobutrol-enhanced MRA	98.0

Blinded reader 1 (n=444/8225)

Group	Value	95% CI
Gadobutrol-enhanced MRA	97.6

Blinded reader 2 (n=457/8844)

Group	Value	95% CI
Gadobutrol-enhanced MRA	97.2

Blinded reader 3 (n=457/9079)

Group	Value	95% CI
Gadobutrol-enhanced MRA	98.0

Clinical investigators (n=457/8926)

Group	Value	95% CI
Gadobutrol-enhanced MRA	99.2

Vessel Diameter (Millimeter [mm]) at the Normal Point and the Narrowest Point in Gadobutrol-Enhanced MRA, Unenhanced MRA and CTA Images Secondary · Images were taken pre-injection and post-injection

The segment reduction in diameter (DIA) of greater than 10% was considered abnormal and measured. The diameter of each of these abnormal segments was measured using electronic calipers (perpendicular to the long axis of the vessel) at the point of most severe stenosis within each segment. Mean of vessel diameters was calculated by segment separately for CTA and MRA readers. For ease of expression, the following abbreviations will be used: Diameter (DIA), Blinded Reader (BR), Clinical Investigator (CI).

Vessel DIA at normal point: BRs

Group	Value	95% CI
Gadobutrol-Enhanced MRA	4.88	± 1.90
Unenhanced MRA	4.33	± 1.53
Computed Tomographic Angiography	4.98	± 2.08

Vessel DIA at narrowest point: BRs

Group	Value	95% CI
Gadobutrol-Enhanced MRA	3.23	± 1.54
Unenhanced MRA	2.66	± 1.34
Computed Tomographic Angiography	3.00	± 1.50

Vessel DIA at normal point: CIs

Group	Value	95% CI
Gadobutrol-Enhanced MRA	4.81	± 1.78
Unenhanced MRA	4.54	± 1.58
Computed Tomographic Angiography	5.17	± 2.02

Vessel DIA at narrowest point: CIs

Group	Value	95% CI
Gadobutrol-Enhanced MRA	2.42	± 1.37
Unenhanced MRA	2.31	± 1.21
Computed Tomographic Angiography	2.68	± 1.62

The Percentage of Segments With Artifacts Presence Secondary · Images were taken pre-injection and post-injection

Artifacts were collected for the MRA images on a segmental basis.

Blinded reader 1

Group	Value	95% CI
Gadobutrol-enhanced MRA	46.6
Unenhanced MRA	97.1

Blinded reader 2

Group	Value	95% CI
Gadobutrol-enhanced MRA	14.0
Unenhanced MRA	54.9

Blinded reader 3

Group	Value	95% CI
Gadobutrol-enhanced MRA	16.2
Unenhanced MRA	41.2

Types of Artifacts on a Segment Basis by Blinded Reader 1 Secondary · Images were taken pre-injection and post-injection

The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example \[eg\], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).

Motion artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	18.6
Unenhanced MRA	41.9

Venous opacification

Group	Value	95% CI
Gadobutrol-enhanced MRA	9.8
Unenhanced MRA	0.8

Saturation artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	21.6
Unenhanced MRA	38.2

Susceptibility artifacts

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.1
Unenhanced MRA	0.2

Ringing artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.5
Unenhanced MRA	29.3

Bolus timing error

Group	Value	95% CI
Gadobutrol-enhanced MRA	4.3
Unenhanced MRA	4.0

Other

Group	Value	95% CI
Gadobutrol-enhanced MRA	9.3
Unenhanced MRA	48.0

Types of Artifacts on a Segment Basis by Blinded Reader 2 Secondary · Images were taken pre-injection and post-injection

The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example \[eg\], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).

Motion artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	5.6
Unenhanced MRA	39.8

Venous opacification

Group	Value	95% CI
Gadobutrol-enhanced MRA	5.7
Unenhanced MRA	0.3

Saturation artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	2.0
Unenhanced MRA	24.5

Susceptibility artifacts

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.8
Unenhanced MRA	3.7

Ringing artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.2
Unenhanced MRA	0.0

Bolus timing error

Group	Value	95% CI
Gadobutrol-enhanced MRA	1.1
Unenhanced MRA	0.0

Other

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.5
Unenhanced MRA	0.3

Types of Artifacts on a Segment Basis by Blinded Reader 3 Secondary · Images were taken pre-injection and post-injection

The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example \[eg\], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).

Motion artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.6
Unenhanced MRA	13.2

Venous opacification

Group	Value	95% CI
Gadobutrol-enhanced MRA	1.7
Unenhanced MRA	0.1

Saturation artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	13.8
Unenhanced MRA	39.4

Susceptibility artifacts

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.2
Unenhanced MRA	0.5

Ringing artifact

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.6
Unenhanced MRA	6.4

Bolus timing error

Group	Value	95% CI
Gadobutrol-enhanced MRA	1.6
Unenhanced MRA	0.4

Other

Group	Value	95% CI
Gadobutrol-enhanced MRA	0.4
Unenhanced MRA	0.1

The Percentage of Location of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA Secondary · Images were taken pre-injection and post-injection

Location within a segment was based on the point of greatest stenosis and was recorded for stenosis \>=70% (including occlusions) as: - At the bifurcation or proximal origin of a segment (occlusion proximal to the origin of the segment); - Within 5 mm of the bifurcation or proximal origin of a segment; - Beyond 5 mm from the bifurcation or proximal origin of a segment.

At the bifurcation: BR 1 (n=353; 89)

Group	Value	95% CI
Gadobutrol-enhanced MRA	50.4
Unenhanced MRA	59.6

At the bifurcation: BR 2 (n=429; 429)

Group	Value	95% CI
Gadobutrol-enhanced MRA	52.2
Unenhanced MRA	58.7

At the bifurcation: BR 3 (n=525; 559)

Group	Value	95% CI
Gadobutrol-enhanced MRA	44.0
Unenhanced MRA	54.2

Within 5 mm of the bifurcation: BR 1 (n=353; 89)

Group	Value	95% CI
Gadobutrol-enhanced MRA	16.7
Unenhanced MRA	12.4

Within 5 mm of the bifurcation: BR 2 (n=429; 429)

Group	Value	95% CI
Gadobutrol-enhanced MRA	14.7
Unenhanced MRA	10.7

Within 5 mm of the bifurcation: BR 3 (n=525; 559)

Group	Value	95% CI
Gadobutrol-enhanced MRA	34.7
Unenhanced MRA	27.0

Beyond 5 mm of the bifurcation: BR 1 (n=353; 89)

Group	Value	95% CI
Gadobutrol-enhanced MRA	32.9
Unenhanced MRA	28.1

Beyond 5 mm of the bifurcation: BR 2 (n=429; 429)

Group	Value	95% CI
Gadobutrol-enhanced MRA	33.1
Unenhanced MRA	30.5

Length of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA Secondary · Images were taken pre-injection and post-injection

The length of stenosis was based on the most proximal (first point) in a segment where a stenosis exceeded 10% and the most distal point (last point) in the segment where a stenosis exceeded 10%. If a stenosis spanned more than one segment then the measurement was only included to the beginning or end (boundary) of the segment being evaluated. If there was no stenosis of \>=70% in a segment then the length was designated as 0.

Reader 1 (n=290; 66)

Group	Value	95% CI
Gadobutrol-enhanced MRA	11.26	± 11.77
Unenhanced MRA	13.36	± 11.47

Reader 2 (n=315; 281)

Group	Value	95% CI
Gadobutrol-enhanced MRA	6.25	± 6.99
Unenhanced MRA	7.18	± 6.07

Reader 3 (n=277; 268)

Group	Value	95% CI
Gadobutrol-enhanced MRA	4.89	± 4.69
Unenhanced MRA	5.36	± 3.76

Adverse events — posted to ClinicalTrials.gov

Time frame: From the time the consent was signed until 24 (+/-6) hours follow-up after the study MRA but was continued until completion of the CTA in those participants who had the CTA performed after the MRA (as part of the study). Reporting threshold: 1%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Gadobutrol (Gadavist, BAY 86-4875)

Serious: 1/479 (0%)

Deaths: —

Serious adverse events (1 terms)

Reaction	System	Gadobutrol (Gadavist, BAY …
Cerebrovascular accident	Nervous system disorders	—

Most-reported serious reactions: Cerebrovascular accident.

Data from ClinicalTrials.gov NCT01344447 adverse events section.

Sponsor's own description

Subjects referred for a routine CTA (computed tomography angiography) or MRA (magnetic resonance angiography) will be invited to participate in the study and subjects will be involved in the study for between 2 and 12 days. Two to three visits to the study doctor will be required.

This study will compare the diagnostic results of Gadobutrol enhanced MRA images with MRA images taken without contrast agent using images from a CTA as the standard of reference, which may have been performed up to 60 days prior to enrolment. If a CTA has not been performed in this prior time period, a CTA is required for the study.

MRA and CTA images will be collected for an independent review (blinded read).

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.