A Study to Assess Regadenoson Administration Following an Inadequate Exercise Stress Test as Compared to Regadenoson Alone for Myocardial Perfusion Imaging (MPI) Using Single Photon Emission Computed Tomography (SPECT)

Phase 3

Completed

Conditions: Coronary Artery Disease (CAD)

Interventions: Drug: Regadenoson
Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)

Registration Number: NCT01618669

Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary: The purpose of this study is to demonstrate that the strength of agreement between single photon emission computed tomography (SPECT) imaging with regadenoson following inadequate exercise stress testing and SPECT imaging with regadenoson alone is not inferior to the strength of agreement between two sequential regadenoson SPECT images without exercise.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1147

Inclusion Criteria

Subjects referred for an exercise or pharmacologic stress test SPECT MPI procedure for the evaluation of coronary artery disease (CAD) are eligible for study participation. Subjects referred for pharmacologic stress should have a reasonable potential of attempting exercise stress. Subject must have one of the following:
- a. Past ischemia on any prior imaging stress test without invasive intervention on the artery subtending this territory
- b. Subject with known CAD who have symptoms similar to previous ischemic symptoms, or recent onset of symptoms or recently worsened symptoms suggestive of ischemia
- c. Diamond Forrester estimated pretest probability of CAD of ≥ 50%
- d. History of most recent coronary artery bypass surgery or most recent percutaneous coronary intervention (PCI) > 10 years (patients who are > 30 days but less than 10 years post coronary artery bypass graft (CABG) or PCI can be included if they meet criteria a, b, or e)
- e. Previously demonstrated 100% occlusion by invasive coronary or computed tomography (CT) angiography without successful intervening revascularization as these foods may alter regadenoson effects

Exclusion Criteria

Subject has a clinically significant illness, medical condition, or laboratory abnormality
Female subject who is pregnant or lactating
Subject is on dialysis for end stage renal disease or has a history of glomerular filtration rate (GFR) < 15 mL/min (calculated using MDRD [Modification of Diet in Renal Disease] formula)
Subject has a history of coronary revascularization by either PCI or CABG within 1 month prior to the rest myocardial perfusion imaging (MPI)
Subject has a pacemaker or an implantable cardioverter defibrillator (ICD)
Subject has a history of acute myocardial infarction (MI) or high risk unstable angina within 30 days prior to the rest MPI or has had cardiac transplantation
Subject has uncontrolled hypertension at any point on Visit 2 prior to exercise testing (i.e., systolic blood pressure (SBP) ≥ 180 or diastolic blood pressure (DBP) ≥ 95 mmHg on two consecutive measurements while at rest).
Subject has severe aortic stenosis or hypertrophic cardiomyopathy with obstruction or has decompensated congestive heart failure
Subject has a history of severe respiratory disease including: asthma, chronic obstructive pulmonary disease (COPD) or other bronchospastic reactive airway disease or who is on 24-hour continuous oxygen

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regadenoson After Peak Exercise	Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)	On Day 1 participants received regadenoson, 0.4 mg in a 5 mL intravenous bolus, 3 minutes after exercise while in walk recovery and then a stress SPECT MPI. One to 14 days later participants received regadenoson at rest and then a stress SPECT MPI.
Regadenoson Alone	Regadenoson	On Day 1 participants received regadenoson, 0.4 mg in a 5 mL intravenous bolus (1 hour after exercise recovery), and then stress SPECT MPI. One to 14 days later participants received regadenoson at rest and then a stress SPECT MPI.
Regadenoson Alone	Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)	On Day 1 participants received regadenoson, 0.4 mg in a 5 mL intravenous bolus (1 hour after exercise recovery), and then stress SPECT MPI. One to 14 days later participants received regadenoson at rest and then a stress SPECT MPI.
Regadenoson After Peak Exercise	Regadenoson	On Day 1 participants received regadenoson, 0.4 mg in a 5 mL intravenous bolus, 3 minutes after exercise while in walk recovery and then a stress SPECT MPI. One to 14 days later participants received regadenoson at rest and then a stress SPECT MPI.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Majority Reader Self-agreement in Ischemia Assessment Between First and Second Stress Scans	Day 1 (rest scan and first stress scan) and Day 2 -15 (second stress scan)	SPECT scans were reviewed in a blinded fashion by 3 independent expert readers using the 17-segment model for standardized myocardial segmentation. At rest and stress, each segment was scored on a 0 (normal) to 4 (absent contrast/radiotracer uptake) scale by each of the 3 blinded readers according to the amount of contrast or radiotracer the myocardium in the segment absorbed. If the stress score was ≥ 2 and the rest score was less than the stress score, the segment was counted as having a reversible defect. The number of segments with reversible defects was categorized as absence (0 - 1 reversible segments) or presence (≥ 2 defects reversible segments) of ischemia. Each reader was defined as having self-agreement based upon identical categorization of a given participant as absent or present for ischemia for both the initial and second stress visits. Majority agreement is if at least 2 out of the 3 blinded readers demonstrated self-agreement for a given participant.

Secondary Outcome Measures

Name	Time	Method
Percentage of Cardiac Segments Obscured by Subdiaphragmatic Activity	Day 1 (stress MPI 1) and Day - 15 (stress MPI 2)	The number of cardiac segments obscured by the sub-diaphragmatic activity by group by stress SPECT MPI scan and by reader is reported.
Percentage of Scans With Subdiaphragmatic Interference	Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2)	Each reader assessed the sub-diaphragmatic radiotracer interference with cardiac image quality using a 4-point scale of 0 = none, 1 = slight, 2 = moderate or 3 = severe for each stress SPECT MPI. The median rating across the 3 readers was used to summarize the percentage of scans with interference.
Proportion of Participants With Agreement in the Assessment of Absence or Presence of Ischemia Between First and Second Stress Scans	Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2)	The number of segments with reversible defects was assessed by each of the 3 blinded independent expert readers. Based on the median count of the number of reversible defects across the 3 readers, categorized as absence (0 to 1 reversible segments) or presence (≥ 2 reversible defects) of ischemia, the proportion of participants with agreement in the presence and absence of ischemia between the first and second stress scans was calculated.
Participants With Less, the Same, or More Reversible Perfusion Defects Shown by the First Stress Scan When Compared to the Second Stress Scan	Day 1 (stress MPI 1) and Day 2-15 (stress MPI 2)	Each reader evaluated the initial stress SPECT MPI scan compared to the participant's second stress SPECT MPI scan (blinded at time of the evaluation) for whether there was Less (-1), the Same (0) or More (1) reversible perfusion defects. The median assessment of the 3 blinded readers was used to summarize the number of participants in each category.
Target to Background Radiotracer Uptake Ratios From the First and Second Stress Scans	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)	Image quality was assessed through radiotracer uptake in the heart (target organ) compared to liver, gut and combined liver plus gut (background interference).
Number of Participants With Adverse Events Within 24 Hours After Administration of Regadenoson	Up to 24 hours after study drug administration for each stress MPI (Day 1 and Day 2-15)	An adverse event is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: * Results in death, * Is life threatening, * Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, * Results in congenital anomaly, or birth defect, * Requires inpatient hospitalization or leads to prolongation of hospitalization * Other medically important events. Relationship to study drug was assessed by the investigator.
Proportion of Participants With Agreement in the Assessment of Reversible Defects in 3 Categories of Ischemia Between First and Second Stress Scans	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)	The number of segments with reversible defects was assessed by each of the 3 blinded independent expert readers. Based on the median count of the number of reversible defects across the 3 readers, categorized as 0 to 1, 2 to 4, or ≥ 5 reversible segments, the proportion of participants with agreement in the three ischemia categories between the first and second stress scans was to be calculated. In the reported data, these proportions only include the 0-1 and 2-4 categories; the ≥ 5 category was not included because there were no participants in this category for the Regadenoson Alone group for the initial stress MPI.
Proportion of Participants With Agreement in the Summed Stress Score (SSS) Between First and Second Stress Scans	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)	The 17-segment model for standardized myocardial segmentation was used to analyze MPI scans. Each segment was scored on a 0 to 4 scale according to the amount of contrast or radiotracer the myocardium in the segment absorbed: * 0: normal perfusion * 1: slightly reduced contrast/radiotracer uptake * 2: moderately reduced contrast/radiotracer uptake * 3: severely reduced contrast/radiotracer uptake * 4: absent contrast/radiotracer uptake. The Summed Stress Score (SSS) was calculated as the sum of the stress scores across the 17 segments. The mean value (rounded to the nearest integer) across the 3 readers was computed and the SSS was categorized into 4 group categorical variables based on the score: 0 to 3, 4 to 7, 8 to 11, and ≥ 12. The proportion of participants with agreement in respect to these categories between the two stress scans was calculated.
Proportion of Participants With Agreement in the Summed Difference Score (SDS) Between First and Second Stress Scans	Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2)	The 17-segment model for standardized myocardial segmentation was used to analyze MPI scans. At rest and stress, each segment was scored on a 0 to 4 scale according to the amount of contrast or radiotracer the myocardium in the segment absorbed: * 0: normal perfusion * 1: slightly reduced contrast/ uptake * 2: moderately reduced contrast/uptake * 3: severely reduced contrast/uptake * 4: absent contrast/uptake. SSS was calculated as the sum of the stress scores across the 17 segments and the Summed Rest Score (SRS) was calculated as the sum of the rest scores across the 17 segments. The Summed Difference Score (SDS) is the difference in the SSS and SRS (SSS - SRS). The mean value (rounded to the nearest integer) across the 3 readers was computed and the SDS was categorized into 3 categorical variables based on the score: 0 to 6, 7 to 13 and ≥ 14. The proportion of participants with agreement in respect to these categories between the two stress scans was calculated.
Overall Assessment of Image Quality	Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2)	The image quality for each scan was rated by each independent reader as 1 = Poor, 2 = Fair, 3 = Good, 4 = Excellent. Based on the median rating of overall image quality across the three readers, the number of participants with each rating is reported for each scan.
Percentage of Participants With Treatment-emergent Clinically Significant Cardiac Events	Within 1 hour for ECG events and up to 24 hours for adverse events after administration of regadenoson	A clinically significant cardiac event is defined as: * Any of the following events found on the Holter electrocardiogram (ECG)/12-Lead ECG within 1 hour after regadenoson administration: * ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes, ventricular flutter), * ST-T depression (\> 2 mm), * ST-T elevation (≥1 mm), * Atrioventricular (AV) block (2:1 AV block, AV Mobitz I, AV Mobitz II, complete heart block) * sinus arrest \> 3 seconds in duration Or * a treatment-emergent adverse event (TEAE) per the Medical Dictionary for Regulatory Activities (MedDRA) Standardised MedDRA Queries (SMQ) (Narrow Scope) for myocardial infarction Or * a TEAE preferred term of angina unstable within 24 hours of regadenoson administration.

Trial Locations

Locations (69): Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
Mobile Heart Specialists, PC
🇺🇸
Mobile, Alabama, United States
HOCC - New Britain Campus
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New Britain, Connecticut, United States
Holy Cross Hospital
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Fort Lauderdale, Florida, United States
Midwest Cardiology Associates
🇺🇸
Overland Park, Kansas, United States
Washington University School of Medicine
🇺🇸
St. Louis, Missouri, United States
Silicon Valley Medical Imaging
🇺🇸
Fremont, California, United States
Long Beach Memorial Medical Center
🇺🇸
Long Beach, California, United States
St. Luke's Cardiology St. Vincent's HealthCare
🇺🇸
Jacksonville, Florida, United States
Ventura Clinical Trials
🇺🇸
Malibu, California, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
University Cardiology Associates, LLC
🇺🇸
Augusta, Georgia, United States
Sanatorio San Geronimo
🇦🇷
Santa Fe, Argentina
Florida Hospital/Cardiovascular Institute
🇺🇸
Orlando, Florida, United States
S & W Clinical Research
🇺🇸
Fort Lauderdale, Florida, United States
MIMA Century Research Associates
🇺🇸
Melbourne, Florida, United States
Westchester Medical Center-New York Medical College
🇺🇸
Valhalla, New York, United States
Watson Medical Clinic/Lakeland Regional Medical Clinic
🇺🇸
Lakeland, Florida, United States
East Coast Institute for Research, LLC
🇺🇸
Jacksonville, Florida, United States
Delaware Clinical Trials
🇺🇸
Wilmington, Delaware, United States
Los Angeles Biomedical Research Institute
🇺🇸
Torrance, California, United States
Elite Research and Clinical Trials
🇺🇸
Aventura, Florida, United States
Santa Rosa Cardiology Medical Group, Inc.
🇺🇸
Santa Rosa, California, United States
Florida Heart Associates
🇺🇸
Fort Myers, Florida, United States
South Coast Medical Group
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Savannah, Georgia, United States
Mission Internal Medical Group
🇺🇸
Mission Viejo, California, United States
Cardiovascular Imaging Technologies
🇺🇸
Kansas City, Missouri, United States
Roanoke Heart Institute, PC
🇺🇸
Roanoke, Virginia, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Laurelton Medical center
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Laurelton, New York, United States
Buffalo Cardiology & Pulmonary Associates, P.C.
🇺🇸
Williamsville, New York, United States
Katy Cardiology Associates
🇺🇸
Katy, Texas, United States
Mission Research Institute LLC
🇺🇸
New Braunfels, Texas, United States
University of Virginia
🇺🇸
Charlottesville, Virginia, United States
Cardiovascular Research Center of South Florida
🇺🇸
Miami, Florida, United States
I U School of Medicine/ Krannert Institute of Cardiology
🇺🇸
Indianapolis, Indiana, United States
VA San Diego Healthcare System
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San Diego, California, United States
Hennepin County Medical Center
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Minneapolis, Minnesota, United States
Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
VA Greater Los Angeles Healthcare System
🇺🇸
Los Angeles, California, United States
Cardiology Partners Clinical Research Institute
🇺🇸
Wellington, Florida, United States
St. Joseph's Hospital
🇺🇸
Atlanta, Georgia, United States
University of Pennsylvania Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
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Pittsburgh, Pennsylvania, United States
University of Washington
🇺🇸
Seattle, Washington, United States
Instituto Nacional Cardiovascular de EsSalud
🇵🇪
Lima, Peru
Yale University
🇺🇸
New Haven, Connecticut, United States
Las Vegas Radiology
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Las Vegas, Nevada, United States
Alfieri Cardiology
🇺🇸
Newark, Delaware, United States
Instituto Oulton
🇦🇷
Cordoba, Argentina
Berkshire Medical Center
🇺🇸
Pittsfield, Massachusetts, United States
Maine Research Associates
🇺🇸
Portland, Maine, United States
Alegent Health Heart and Vascular Specialists
🇺🇸
Omaha, Nebraska, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Hospital Arzobispo Loayza
🇵🇪
Lima, Peru
Wayne State University
🇺🇸
Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸
Detriot, Michigan, United States
Michigan Heart
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Ypsilanti, Michigan, United States
Cardiology Associates of North Mississippi
🇺🇸
Tupelo, Mississippi, United States
Alegent Health Research Center
🇺🇸
Omaha, Nebraska, United States
Hospital Italiano Garibaldi
🇦🇷
Rosario, Santa Fé, Argentina
Clinica Anglo Americana
🇵🇪
Lima, Peru
Instituto de Cardiologia la Plata
🇦🇷
La Plata, Argentina
Hospital Italiano de La Plata
🇦🇷
Provincia de Buenos Aires, Argentina
VA Caribbean Healthcare System (672)
🇵🇷
San Juan, Puerto Rico
Westside Medical Associates of Los Angeles
🇺🇸
Los Angeles, California, United States
University of South Florida
🇺🇸
Tampa, Florida, United States
Berks Cardiologists, Ltd.
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Wyomissing, Pennsylvania, United States
West Houston Area Clinical Trial Consultants, LLC
🇺🇸
Tomball, Texas, United States