Gadobutrol/Gadavist-enhanced Cardiac Magnetic Resonance Imaging (CMRI) to Detect Coronary Artery Disease (CAD) (GadaCAD 1)

• ClinicalTrials.gov Identifier: NCT01890421
• Recruitment Status: Completed
• First Posted: July 1, 2013
• Results First Posted: May 16, 2018
• Last Update Posted: May 16, 2018
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

Brief Summary:

Participants being evaluated for suspected or known Coronary artery Disease (CAD) based on signs and/or symptoms, will be invited to participate in the study. The duration for a participant in the study may range from 2 days to 4-6 weeks. One to four visits to the study doctor will be required.

This study will investigate the diagnostic results of gadobutrol-enhanced Cardiac Magnetic Resonance Imaging (CMRI) images regarding the detection (sensitivity) and exclusion (specificity) of coronary artery disease utilizing a uniform image acquisition software. The CMR images will be tested either against the results from routine clinical Coronary Angiography (CA) or those from Computed Tomography Angiography (CTA), which is used as the standard of reference. The CA/CTA may have been performed up to 4 weeks prior to enrollment or be scheduled up to 4/6 weeks after the study.

CMRI and CA/CTA images will be collected for an independent image review (blinded read).

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Drug: Gadobutrol (Gadovist, Gadavist, BAY86-4875)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 426 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Multicenter Open-label Study to Evaluate Efficacy of Gadobutrol-enhanced Cardiac Magnetic Resonance Imaging (CMRI) for Detection of Significant Coronary Artery Disease (CAD) in Subjects With Known or Suspected CAD by a Blinded Image Analysis
• Actual Study Start Date: July 19, 2013
• Actual Primary Completion Date: April 10, 2015
• Actual Study Completion Date: August 31, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Gadobutrol 0.1 mmol/kg body weight; Participants received gadobutrol at the total approved standard dose of 0.1 millimole per kilogram body weight (mmol/kg BW) in 2 separate bolus injections: 0.05 mmol/kg BW at peak pharmacologic stress and 0.05 mmol/kg BW at rest via a power injector.	Drug: Gadobutrol (Gadovist, Gadavist, BAY86-4875); Participants received gadobutrol at the total approved standard dose of 0.1 millimole per kilogram body weight (mmol/kg BW) in 2 separate bolus injections: 0.05 mmol/kg BW at peak pharmacologic stress and 0.05 mmol/kg BW at rest via a power injector.

Outcome Measures

Primary Outcome Measures :

1. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI (Based on RPS) - Primary Analysis of Sensitivity Based on Blinded Readers' Assessment [ Time Frame: 0 to 30/40 minute (min) post-injection ]
   Blinded readers evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest)]. A myocardial region a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=50% for primary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Sensitivity= true positive/ (true positive + false negative).
2. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI (Based on RPS) - Additional Secondary Analysis of Sensitivity Based on the Blinded Readers' Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Blinded readers evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest)]. A myocardial region a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=70% for secondary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Sensitivity= true positive/ (true positive + false negative). This additional secondary analysis of sensitivity was prospective analysis.
3. Absence of a Myocardial Perfusion Defect Excluding Significant CAD Per Participant on Gadobutrol-enhanced CMRI (Based on RPS) - Primary Analysis of Specificity Based on the Blinded Readers' Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Blinded readers evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest)]. A myocardial region a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=50% for primary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Specificity= true negative/ (true negative + false positive).
4. Absence of a Myocardial Perfusion Defect Excluding Significant CAD Per Participant on Gadobutrol-enhanced CMRI (Based on RPS) - Additional Secondary Analysis of Specificity Based on the Blinded Readers' Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Blinded readers evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest)]. A myocardial region a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=70% for primary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Specificity= true negative/ (true negative + false positive). This additional secondary analysis of specificity was prospective analysis.
5. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI Versus Unenhanced Wall Motion CMRI Images - Primary Analysis of Sensitivity Comparison Based on the Blinded Readers' Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI versus the presence of wall motion abnormalities on unenhanced CMRI images (based on regional perfusion/regional wall motion score of the 6 myocardial regions) was calculated by blinded readers' assessment. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=50% for primary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Sensitivity= true positive/ (true positive + false negative).
6. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI Versus Unenhanced Wall Motion CMRI Images - Additional Secondary Analysis of Sensitivity Comparison Based on the Blinded Readers' Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI versus the presence of wall motion abnormalities on unenhanced CMRI images (based on regional perfusion/regional wall motion score of the 6 myocardial regions) was calculated by blinded readers' assessment. Significant CAD was defined as quantitative coronary angiography (QCA) stenosis of >=70% for primary analysis, and was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) verified by standard of reference (SoR). Sensitivity= true positive/ (true positive + false negative). This additional secondary analysis of sensitivity was prospective analysis.

Secondary Outcome Measures :

1. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI - Secondary Analysis of Sensitivity Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI versus the presence of wall motion abnormalities on unenhanced CMRI images (based on regional perfusion/regional wall motion score of the 6 myocardial regions) was calculated by investigator's assessment. Significant CAD was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI or the presence of wall motion abnormalities on unenhanced CMRI images verified by SoR (significant CAD defined as QCA stenosis of >=50%). Sensitivity= true positive/ (true positive + false negative).
2. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI - Additional Secondary Analysis of Sensitivity Comparison Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI versus the presence of wall motion abnormalities on unenhanced CMRI images (based on regional perfusion/regional wall motion score of the 6 myocardial regions) was calculated by investigator's assessment. Significant CAD was determined based on the presence of a myocardial perfusion defect on gadobutrol-enhanced CMRI or the presence of wall motion abnormalities on unenhanced CMRI images verified by SoR (significant CAD defined as QCA stenosis of >=70%). Sensitivity= true positive/ (true positive + false negative). This additional secondary analysis of sensitivity was prospective analysis.
3. Absence of a Myocardial Perfusion Defect Excluding Significant CAD Per Participant on Gadobutrol-enhanced CMRI - Secondary Analysis of Specificity Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Investigator's assessment evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest). A myocardial region was rated to have a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. The investigator's assessment of participant-based specificity of gadobutrol-enhanced CMRI was analyzed with significant CAD defined as maximum stenosis severity of >=50% by QCA, which were secondary analysis. Specificity= true negative/ (true negative + false positive).
4. Absence of a Myocardial Perfusion Defect Excluding Significant CAD Per Participant on Gadobutrol-enhanced CMRI - Additional Secondary Analysis of Specificity Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Investigator's assessment evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest). A myocardial region was rated to have a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. The investigator's assessment of participant-based specificity of gadobutrol-enhanced CMRI was analyzed with significant CAD defined as maximum stenosis severity of >=70% by QCA, which were secondary analysis. Specificity= true negative/ (true negative + false positive). This additional secondary analysis of specificity was prospective analysis.
5. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI Versus Unenhanced Wall Motion CMRI Images - Secondary Analysis of Sensitivity Comparison Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Investigator's assessment evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest). A myocardial region was rated to have a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. The investigator's assessment of participant-based sensitivity and specificity of gadobutrol-enhanced CMRI was analyzed with significant CAD defined as maximum stenosis severity of >=50% by QCA, which were secondary analysis. Sensitivity= true positive/ (true positive + false negative).
6. Presence of a Myocardial Perfusion Defect Indicating Significant CAD Per Participant on Gadobutrol-enhanced CMRI Versus Unenhanced Wall Motion CMRI Images - Additional Secondary Analysis of Sensitivity Comparison Based on Investigator's Assessment [ Time Frame: 0 to 30/40 min post-injection ]
   Investigator's assessment evaluated 6 myocardial regions based on regional perfusion score (RPS), 0=normal; 1=abnormal, reversible perfusion defect (stress); 2=abnormal, mixed perfusion defect (reversible and fixed/permanent components); 3=abnormal, fixed/permanent perfusion defect/scar (stress and rest). A myocardial region was rated to have a perfusion defect in case of a RPS of >=1 and was rated to have normal perfusion in case of a RPS of 0. The investigator's assessment of participant-based sensitivity and specificity of gadobutrol-enhanced CMRI was analyzed with significant CAD defined as maximum stenosis severity of >=70% by QCA, which were secondary analysis. Sensitivity= true positive/ (true positive + false negative). This additional secondary analysis of sensitivity was prospective analysis.
7. Localization of a Myocardial Perfusion Defect to a Coronary Territory on Gadobutrol-Enhanced CMRI - Secondary Analysis of Sensitivity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
   Sensitivity was calculated coronary territory based, a coronary territory (left anterior descending artery [LAD] / non-LAD / right coronary artery [RCA] / left circumflex artery [LCX]) was rated positive for significant CAD (significant CAD defined as QCA stenosis of>=50%), if >=1 myocardial region within the same coronary territory showed a myocardial perfusion defect with a RPS of >=1. A coronary territory(LAD / non-LAD) was rated negative for significant CAD, if no myocardial region within the respective coronary territory showed a myocardial perfusion defect (RPS 0). Sensitivity was displayed for all 3 blinded readers and the investigator.
8. Localization of a Myocardial Perfusion Defect to a Coronary Territory on Gadobutrol-enhanced CMRI - Additional Secondary Analysis of Sensitivity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
   Sensitivity was calculated coronary territory based, a coronary territory (LAD / non-LAD / RCA / LCX) was rated positive for significant CAD (significant CAD defined as QCA stenosis of >=70%), if >=1 myocardial region within the same coronary territory showed a myocardial perfusion defect with a RPS of >=1. A coronary territory (LAD / non-LAD) was rated negative for significant CAD, if no myocardial region within the respective coronary territory showed a myocardial perfusion defect (RPS 0). Sensitivity was displayed for all 3 blinded readers and the investigator. This additional secondary analysis of sensitivity was prospective analysis.
9. Localization of a Myocardial Perfusion Defect to a Coronary Territory on Gadobutrol-enhanced CMRI - Secondary Analysis of Specificity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
   Specificity was calculated coronary territory based, a coronary territory (LAD / non-LAD / RCA / LCX) was rated positive for significant CAD (significant CAD defined as QCA stenosis of >=50%), if >=1 myocardial region within the same coronary territory showed a myocardial perfusion defect with a RPS of >=1. A coronary territory (LAD / non-LAD) was rated negative for significant CAD, if no myocardial region within the respective coronary territory showed a myocardial perfusion defect (RPS 0). Specificity was displayed for all 3 blinded readers and the investigator.
10. Localization of a Myocardial Perfusion Defect to a Coronary Territory on Gadobutrol-enhanced CMRI - Additional Secondary Analysis of Specificity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
    Specificity was calculated coronary territory based, a coronary territory (LAD / non-LAD / RCA / LCX) was rated positive for significant CAD (significant CAD defined as QCA stenosis of >=70%), if >=1 myocardial region within the same coronary territory showed a myocardial perfusion defect with a RPS of >=1. A coronary territory (LAD / non-LAD) was rated negative for significant CAD, if no myocardial region within the respective coronary territory showed a myocardial perfusion defect (RPS 0). Specificity was displayed for all 3 blinded readers and the investigator. This additional secondary analysis of specificity was prospective analysis.
11. Detection of Myocardial Perfusion Defect(s) on Gadobutrol-enhanced CMRI in Participants With Significant LMS Stenosis - Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
    Sensitivity was calculated for detection of myocardial perfusion defects on gadobutrol-enhanced CMRI in participants with significant left main stem (LMS) stenosis and the myocardial perfusion defect pattern was described. If >=1 myocardial region showed a myocardial perfusion defect with a RPS of >=1, participants will be rated positive for significant CAD (significant CAD defined as QCA stenosis of >=50%). Sensitivity= true positive/ (true positive + false negative).
12. Presence/Absence of a MPD Indicating/Excluding Significant CAD in Participants With Multi Versus Single Vessel Disease Evaluated on Gadobutrol-enhanced CMRI-Secondary Analysis of Sensitivity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
    Sensitivity was calculated for detection of myocardial perfusion defects (MPD) on gadobutrol-enhanced CMRI in participants with single and multi-vessel diseases. If >=1 myocardial region showed a myocardial perfusion defect with a RPS of >=1, participants will be rated positive for significant CAD (significant CAD defined as QCA stenosis of >=50%). Sensitivity= true positive/ (true positive + false negative).
13. Presence/Absence of a MPD Indicating/Excluding Significant CAD in Participants With Multi Vs Single Vessel Disease Evaluated on Gadobutrol-enhanced CMRI-Additional Secondary Analysis of Sensitivity Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
    Sensitivity was calculated for detection of MPD on gadobutrol-enhanced CMRI in participants with single and multi-vessel diseases. If >=1 myocardial region showed a myocardial perfusion defect with a RPS of >=1, participants will be rated positive for significant CAD (significant CAD defined as QCA stenosis of >=70%). Sensitivity= true positive/ (true positive + false negative). This additional secondary analysis of sensitivity was prospective analysis.
14. Percentage of Participants by Their Lowest Confidence in Diagnosis Obtained on Gadobutrol-enhanced CMRI and Unenhanced Wall Motion CMRI - Based on Blinded Readers' and Investigator's Assessments [ Time Frame: 0 to 30/40 min post-injection ]
    Score for confidence in diagnosis (not confident, somewhat confident, and confident) was described descriptively for each of the 6 myocardial regions. The frequency over the worst confidence in diagnosis obtained within a participant was displayed. All these analyses were done separately for gadobutrol-enhanced CMRI and unenhanced wall motion CMRI.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female participants aged ≥18 years
• Participants with suspected or known CAD based on signs and/or (typical or atypical) chest pain who have routine CA without intervention or CTA within 4 weeks around gadobutrol-enhanced CMRI
• Willingness to undergo stress/rest CMRI and to follow directions and complete all study procedures
• Women of childbearing potential (e.g. age < 60y, no history of surgical sterilization or hysterectomy): use of contraception and a negative pregnancy test

Exclusion Criteria:

• Suspected clinical instability or unpredictability of the clinical course during the study period
• Contraindication to the cardiac MRI examination (e.g. inability to hold breath; severe claustrophobia, metallic devices such as pace makers)
• History of severe allergic or anaphylactoid reaction to any allergen including drugs and contrast agents according to the investigator's assessment / judgment
• Estimated glomerular filtration rate (eGFR) value <30 mL/min/1.73 m^2 derived from a serum / blood creatinine result within 2 weeks prior to gadobutrol injection. Any participant on hemodialysis or peritoneal dialysis is excluded from enrollment.
• Acute renal insufficiency
• Coronary artery bypass grafting (CABG)
• Acute myocardial infarction (< 14 days prior to inclusion), unstable angina / acute coronary syndrome, severe congestive heart failure
• Irregular heart rhythm
• Condition that precludes the safe administration of pharmacological stressor according to the respective approved label such as sinus node disease, 2nd or 3rd degree atrioventricular block, obstructive lung disease

Contacts and Locations

Locations

United States, Minnesota

Minneapolis, Minnesota, United States, 55455

France

Marseille, France, 13385

Saint-Etienne, France, 42055

Germany

Bad Krozingen, Baden-Württemberg, Germany, 79189

Stuttgart, Baden-Württemberg, Germany, 70376

Tuebingen, Baden-Württemberg, Germany, 72076

Darmstadt, Hessen, Germany, 64287

Göttingen, Niedersachsen, Germany, 37075

Bonn, Nordrhein-Westfalen, Germany, 53115

Essen, Nordrhein-Westfalen, Germany, 45122

Leipzig, Sachsen, Germany, 04289

Berlin, Germany, 10709

Berlin, Germany, 12203

Berlin, Germany, 13125

Korea, Republic of

Incheon, Korea, Republic of, 21565

Seoul, Korea, Republic of, 05030

Seoul, Korea, Republic of, 05505

Yangsan-si, Korea, Republic of, 50612

New Zealand

Auckland, New Zealand

Switzerland

Lugano, Ticino, Switzerland, 6900

United Kingdom

Leicester, United Kingdom, LE3 9QP

Liverpool, United Kingdom, L14 3PE

London, United Kingdom, SW3 6NP

Sponsors and Collaborators

Bayer

Investigators

• Study Director: Bayer Study Director; Bayer

More Information

Additional Information:

Click here to find information about studies related to Bayer Healthcare products conducted in Europe. 

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01890421
• Other Study ID Numbers: 15961; 2012-002563-10 ( EudraCT Number )
• First Posted: July 1, 2013
• Results First Posted: May 16, 2018
• Last Update Posted: May 16, 2018
• Last Verified: April 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:

Myocardial Perfusion Imaging

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases