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Gadobutrol Enhanced MRA of the Supra-aortic Vessels (GEMSAV)

Primary Purpose

Carotid Stenosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Gadobutrol (Gadovist, BAY86-4875)

About this trial

This is an interventional diagnostic trial for Carotid Stenosis focused on measuring Supra-aortic vascular disease, MRA, CTA, Males and females aged 18 years or older, Stroke, Transient Ischemic Attack (TIA)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female subjects, aged 18 years and older
Any of the following:
- Known or suspected supra-aortic arterial disease based on:
  - Prior stroke
  - Transient ischemic attack (TIA)
  - Amaurosis Fugax (transient monocular blindness)
- Referred for evaluation of any supra-aortic vessel (for clinically significant stenosis)
- Follow-up for a stent in a supra-aortic vessel
- Prior imaging study (CTA or ultrasound) showing ≥ 50% stenosis of a supra-aortic vessel segment (within 60 days before consent). The proportion of subjects with positive disease (determined by the investigator, based on CTA or ultrasound) will be monitored during the study, and enrolment may be further restricted to require ≥ 70% stenosis to ensure that overall there are an adequate number of subjects with clinically significant disease for the evaluation of study endpoints.
Willingness to undergo the routine Contrast Enhanced Magnetic Resonance Angiography [CE MRA] examination with gadobutrol
Willingness and ability to follow directions and complete all study procedures specified in the protocol
Females of childbearing potential only: Negative pregnancy test on the day of the MRA before the administration of study drug

Exclusion Criteria:

Pregnant or nursing (including pumping for storage and feeding)
Received any other investigational product or participation in any other clinical trial within 30 days before enrollment into this study
Previous enrollment into this study or into any other Bayer sponsored study using gadobutrol
Contraindication to the MRA examinations (e.g. inability to hold breath; severe arrhythmias; very low cardiac output, severe claustrophobia, defibrillators or other metallic devices not approved for MRI)
Contraindication to the use of Gd-containing contrast agents (including subjects with suspicion for or known to have Nephrogenic Systemic Fibrosis [NSF])
History of severe allergic or anaphylactoid reaction to any allergen including drugs and contrast agents
Received any contrast agent within 72 hours before the study MRA, or scheduled receipt of any contrast agent within 24 hours after the study MRA (Note: This applies also to a CTA potentially scheduled during the course of the study.)
Estimated glomerular filtration rate (eGFR) value < 30 ml/min/1.73 m2 derived from a serum creatinine result within 2 weeks before the gadobutrol injection. Any subject on hemodialysis or peritoneal dialysis is excluded from participation. Use the value obtained prior to and closest to the time of the MRA, if there are multiple creatinine values. (Do not use the core lab value if not available prior to the MRA.)
Acute renal insufficiency of any intensity, either due to hepato-renal syndrome or occurring in the peri-operative liver transplantation period
Severe cardiovascular disease (e.g. acute myocardial infarction [< 14 days], unstable angina, congestive heart failure New York Heart Association class IV) or known long QT syndrome
Suspected clinical instability or unpredictability of the clinical course during the study period (e.g. due to previous surgery)
Scheduled or potentially expected for the period between the CTA and gadobutrol MRA:
- Any procedure that may alter the MRA or CTA interpretation, or
- Any interventional or surgical procedure involving the supra-aortic vessels

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm 1

Arm Description

Outcomes

Primary Outcome Measures

Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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.

Sensitivity for Detection of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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.

Specificity for Exclusion of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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.

Minimum Gadobutrol Performance for Sensitivity: Sensitivity > 50%

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.

Minimum Gadobutrol Performance for Specificity: Specificity > 50%

Secondary Outcome Measures

Vessel Diameter (Millimeter [mm]) at the Normal Point and the Narrowest Point in Gadobutrol-Enhanced MRA, Unenhanced MRA and CTA Images

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).

The Percentage of Segments With Artifacts Presence

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

Types of Artifacts on a Segment Basis by Blinded Reader 1

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).

Types of Artifacts on a Segment Basis by Blinded Reader 2

Types of Artifacts on a Segment Basis by Blinded Reader 3

The Percentage of Location of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA

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.

Length of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA

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.

The Percentage of Presence of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease

Each segment was assessed for secondary signs of stenosis for diagnosis of clinically significant disease. The following indicators were considered for the MRA studies: - post-stenotic dilation or ulceration (segmental), - post-stenotic signal dropout, narrowing and intensity reduction, and - thrombus. Each of the three parameters were assessed as present or absent in the region distal to the stenosis. If they were found in any segment distal to the stenosis then they were assessed as present.

Type of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease

Diagnostic Confidence by the Blinded Readers Using Gadobutrol-Enhanced MRA and Unenhanced MRA

Diagnostic confidence was evaluated to determine the level of certainty that the blinded readers assigned to a diagnosis for each segment. This was defined as the degree of confidence that the information on the MRA images represented the true and complete clinical picture of a particular segment. The degree of confidence was rated on a 4-point scale: 1 = Not confident, 2 = Somewhat confident, 3 = Confident, and 4 = Very confident.

The Percentage of Participants With Additional Imaging Studies Recommended by the Blinded Readers and the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images

A measure of diagnostic value was the reduction in the number of additional diagnostic imaging studies recommended/ordered. The clinical investigators and the blinded readers were asked if they would have recommended an additional imaging study for each participant and was recorded.

Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 1

An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study.

Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 2

Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images - Blinded Reader 3

Types of Additional Imaging Studies Recommended by the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images

Full Information

NCT ID

NCT01344447

First Posted

April 5, 2011

Last Updated

December 10, 2018

Sponsor

Bayer

1. Study Identification

Unique Protocol Identification Number

NCT01344447

Brief Title

Gadobutrol Enhanced MRA of the Supra-aortic Vessels

Acronym

GEMSAV

Official Title

Multicenter, Open-label Study to Evaluate the Safety and Efficacy (by Blinded Reading) of Contrast-Enhanced Magnetic Resonance Angiography (MRA) After a Single Intravenous Injection of 0.1 mmol/kg Gadobutrol in Subjects With Known or Suspected Vascular Disease of the Supra-aortic Vessels

Study Type

Interventional

2. Study Status

Record Verification Date

December 2018

Overall Recruitment Status

Completed

Study Start Date

May 12, 2011 (Actual)

Primary Completion Date

May 28, 2014 (Actual)

Study Completion Date

May 28, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bayer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carotid Stenosis

Keywords

Supra-aortic vascular disease, MRA, CTA, Males and females aged 18 years or older, Stroke, Transient Ischemic Attack (TIA)

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

479 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Gadobutrol (Gadovist, BAY86-4875)

Intervention Description

A single bolus injection of approx. 0.1mmol/kg

Primary Outcome Measure Information:

Title

Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA

Description

Time Frame