EXERRT: 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)

• Sponsor: Astellas Pharma Global Development, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01618669
• Collaborator: (none)
• Enrollment: 1,147
• Locations: 69
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 16.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease (CAD)	Drug: Regadenoson; Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1147 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Phase 3b, Open-Label, Parallel Group, Randomized, Multicenter 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)
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regadenoson After Peak Exercise 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.	Drug: Regadenoson; Administered as an intravenous (IV) bolus; Other Names: Lexiscan CVT3146 ; Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)
Active Comparator: Regadenoson Alone 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.	Drug: Regadenoson; Administered as an intravenous (IV) bolus; Other Names: Lexiscan CVT3146 ; Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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).

9. 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.

10. 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.

11. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

• 1. Past ischemia on any prior imaging stress test without invasive intervention on the artery subtending this territory
• 1. Subject with known CAD who have symptoms similar to previous ischemic symptoms, or recent onset of symptoms or recently worsened symptoms suggestive of ischemia
• 1. Diamond Forrester estimated pretest probability of CAD of ≥ 50%
• 1. 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)
• 1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mobile Heart Specialists, PC	Mobile	Alabama	United States	36608
2	Silicon Valley Medical Imaging	Fremont	California	United States	94538
3	Long Beach Memorial Medical Center	Long Beach	California	United States	90806
4	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
5	VA Greater Los Angeles Healthcare System	Los Angeles	California	United States	90073
6	Westside Medical Associates of Los Angeles	Los Angeles	California	United States	90211
7	Ventura Clinical Trials	Malibu	California	United States	90265
8	Mission Internal Medical Group	Mission Viejo	California	United States	92691
9	VA San Diego Healthcare System	San Diego	California	United States	92161
10	Santa Rosa Cardiology Medical Group, Inc.	Santa Rosa	California	United States	95405
11	Los Angeles Biomedical Research Institute	Torrance	California	United States	22908
12	HOCC - New Britain Campus	New Britain	Connecticut	United States	06050
13	Yale University	New Haven	Connecticut	United States	06510
14	Alfieri Cardiology	Newark	Delaware	United States	19713
15	Delaware Clinical Trials	Wilmington	Delaware	United States	19808
16	Elite Research and Clinical Trials	Aventura	Florida	United States	33180
17	S & W Clinical Research	Fort Lauderdale	Florida	United States	33306
18	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
19	Florida Heart Associates	Fort Myers	Florida	United States	33907
20	East Coast Institute for Research, LLC	Jacksonville	Florida	United States	32216
21	St. Luke's Cardiology St. Vincent's HealthCare	Jacksonville	Florida	United States	32216
22	Watson Medical Clinic/Lakeland Regional Medical Clinic	Lakeland	Florida	United States	33805
23	MIMA Century Research Associates	Melbourne	Florida	United States	32901
24	Cardiovascular Research Center of South Florida	Miami	Florida	United States	33173
25	Florida Hospital/Cardiovascular Institute	Orlando	Florida	United States	32803
26	University of South Florida	Tampa	Florida	United States	33620
27	Cardiology Partners Clinical Research Institute	Wellington	Florida	United States	33449
28	St. Joseph's Hospital	Atlanta	Georgia	United States	30342
29	University Cardiology Associates, LLC	Augusta	Georgia	United States	30901
30	South Coast Medical Group	Savannah	Georgia	United States	31406
31	Rush University Medical Center	Chicago	Illinois	United States	60612
32	I U School of Medicine/ Krannert Institute of Cardiology	Indianapolis	Indiana	United States	46202
33	Midwest Cardiology Associates	Overland Park	Kansas	United States	66209
34	Maine Research Associates	Portland	Maine	United States	04210
35	University of Maryland	Baltimore	Maryland	United States	21207
36	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
37	Berkshire Medical Center	Pittsfield	Massachusetts	United States	01201
38	Henry Ford Hospital	Detriot	Michigan	United States	48202
39	Wayne State University	Detroit	Michigan	United States	48201
40	Michigan Heart	Ypsilanti	Michigan	United States	48197
41	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55455
42	Cardiology Associates of North Mississippi	Tupelo	Mississippi	United States	38801
43	Cardiovascular Imaging Technologies	Kansas City	Missouri	United States	64111
44	Washington University School of Medicine	St. Louis	Missouri	United States	63110
45	Alegent Health Heart and Vascular Specialists	Omaha	Nebraska	United States	68124
46	Alegent Health Research Center	Omaha	Nebraska	United States	68124
47	Las Vegas Radiology	Las Vegas	Nevada	United States	89113
48	Laurelton Medical center	Laurelton	New York	United States	11422
49	Columbia University Medical Center	New York	New York	United States	10032
50	Westchester Medical Center-New York Medical College	Valhalla	New York	United States	10595
51	Buffalo Cardiology & Pulmonary Associates, P.C.	Williamsville	New York	United States	14221
52	University of Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19104
53	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
54	Berks Cardiologists, Ltd.	Wyomissing	Pennsylvania	United States	19610
55	Katy Cardiology Associates	Katy	Texas	United States	77493
56	Mission Research Institute LLC	New Braunfels	Texas	United States	78130
57	West Houston Area Clinical Trial Consultants, LLC	Tomball	Texas	United States	77375
58	University of Virginia	Charlottesville	Virginia	United States	22908
59	Roanoke Heart Institute, PC	Roanoke	Virginia	United States	24014
60	University of Washington	Seattle	Washington	United States	98195
61	Hospital Italiano Garibaldi	Rosario	Santa Fé	Argentina	S2000ODA
62	Instituto Oulton	Cordoba		Argentina	X5000JJS
63	Instituto de Cardiologia la Plata	La Plata		Argentina	B1925XAC
64	Hospital Italiano de La Plata	Provincia de Buenos Aires		Argentina	B1900AX
65	Sanatorio San Geronimo	Santa Fe		Argentina	S3001XAF
66	Clinica Anglo Americana	Lima		Peru	Lima 27
67	Hospital Arzobispo Loayza	Lima		Peru
68	Instituto Nacional Cardiovascular de EsSalud	Lima		Peru
69	VA Caribbean Healthcare System (672)	San Juan		Puerto Rico	00921

Sponsors and Collaborators

• Astellas Pharma Global Development, Inc.

Investigators

• Study Director: Senior Medical Director, Astellas Pharma Global Development, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to results on Astellas Clinical Study Results Web site

Publications

None provided.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT01618669
• Other Study ID Numbers: 3606-CL-3004
• First Posted: Jun 13, 2012
• Last Update Posted: Feb 8, 2016
• Last Verified: Jan 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Astellas Pharma Global Development, Inc.: Coronary Artery Disease (CAD); regadenoson; pharmacologic stress
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Regadenoson

Study Results

Participant Flow

Recruitment Details	This study was conducted at 49 sites in a total of 3 countries including the United States (44 sites), Argentina (4 sites) and Peru (1 site).
Pre-assignment Detail	At Baseline, patients meeting all inclusion/exclusion criteria completed single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) while at rest. Participants then underwent a Bruce or modified Bruce exercise protocol; those unable to reach 85% maximum predicted heart rate and/or 5 metabolic equivalents were randomized.

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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 myocardial perfusion imaging (MPI). One to 14 days later participants received regadenoson at rest and then a stress SPECT 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.
Period Title: Overall Study
STARTED	578	569
Received Treatment	575	567
COMPLETED	544	546
NOT COMPLETED	34	23

Baseline Characteristics

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	575	567	1142
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (11.45)	61.9 (11.19)	61.9 (11.32)
Sex: Female, Male (Count of Participants)
Female	234 40.7%	239 42.2%	473 41.4%
Male	341 59.3%	328 57.8%	669 58.6%
Bruce Exercise Group (participants) [Number]
Standard Bruce Exercise	448 77.9%	442 78%	890 77.9%
Modified Bruce Exercise	90 15.7%	93 16.4%	183 16%
Maximum Metabolic Equivalents Achieved (metabolic equivalents) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [metabolic equivalents]	5.45 (2.284)	5.37 (2.331)	5.41 (2.307)

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With Majority Reader Self-agreement in Ischemia Assessment Between First and Second Stress Scans
Description	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.
Time Frame	Day 1 (rest scan and first stress scan) and Day 2 -15 (second stress scan)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Number (95% Confidence Interval) [proportion of participants]	0.92 0.2%	0.95 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regadenoson After Peak Exercise, Regadenoson Alone
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If the lower confidence bound of the 1-sided alpha level of 0.025 of the difference in the proportion of participants with majority reader self-agreement exceeded -0.075, non-inferiority would be demonstrated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.06 to -0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.015
	Estimation Comments	Difference equals Regadenoson After Peak Exercise minus Regadenoson Alone

2. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent Clinically Significant Cardiac Events
Description	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.
Time Frame	Within 1 hour for ECG events and up to 24 hours for adverse events after administration of regadenoson

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomized participants who received at least 1 dose of regadenoson study drug)

Arm/Group Title	Regadenoson After Peak Exercise: MPI 1	Regadenoson After Peak Exercise: MPI 2	Regadenoson Alone: MPI 1	Regadenoson Alone: MPI 2
Arm/Group Description	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.	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.	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.	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.
Measure Participants	575	544	567	548
Any Event	3.0 0.5%	0.9 0.2%	0.5 0%	0.4 NaN
Any Holter/12-Lead ECG Abnormality	2.8 0.5%	0.9 0.2%	0.5 0%	0.4 NaN
Sustained Ventricular Tachycardia	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Ventricular Fibrillation or Ventricular Flutter	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Torsade de Pointes	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
ST-T Depression (≥ 2 mm)	2.3 0.4%	0.6 0.1%	0.4 0%	0.4 NaN
ST-T Elevation (≥ 1 mm)	0.5 0.1%	0.4 0.1%	0.2 0%	0.0 NaN
2:1 AV Block	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Mobitz I Second Degree AV Block	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Mobitz II Second Degree AV Block	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Complete Heart Block	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Pause > 3.0 seconds	0.0 0%	0.0 0%	0.0 0%	0.0 NaN
Any TEAE per SMQ for Myocardial Infarction	0.3 0.1%	0.0 0%	0.0 0%	0.0 NaN
Acute Coronary Syndrome	0.2 0%	0.0 0%	0.0 0%	0.0 NaN
Myocardial Infarction	0.2 0%	0.0 0%	0.0 0%	0.0 NaN
Adverse Event of Angina Unstable	0.0 0%	0.0 0%	0.0 0%	0.0 NaN

3. Secondary Outcome

Title	Proportion of Participants With Agreement in the Assessment of Absence or Presence of Ischemia Between First and Second Stress Scans
Description	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.
Time Frame	Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Number (95% Confidence Interval) [proportion of participants]	0.75 0.1%	0.77 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regadenoson After Peak Exercise, Regadenoson Alone
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The lower confidence bound of the 1-sided alpha level of 0.025 of the difference in agreement rates must exceed -0.10 in order to demonstrate non-inferiority.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.063
	Estimation Comments	Difference equals Regadenoson After Peak Exercise minus Regadenoson Alone

4. Secondary Outcome

Title	Proportion of Participants With Agreement in the Assessment of Reversible Defects in 3 Categories of Ischemia Between First and Second Stress Scans
Description	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.
Time Frame	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Number (95% Confidence Interval) [proportion of participants]	0.73 0.1%	0.75 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regadenoson After Peak Exercise, Regadenoson Alone
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The lower confidence bound of the 1-sided alpha level of 0.025 of the difference in agreement rates must exceed -0.133 in order to demonstrate non-inferiority. Non-inferiority could not be assessed because of insufficient data in the Regadenoson Alone group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments

5. Secondary Outcome

Title	Proportion of Participants With Agreement in the Summed Stress Score (SSS) Between First and Second Stress Scans
Description	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.
Time Frame	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Number [proportion of participants]	0.86 0.1%	0.84 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regadenoson After Peak Exercise, Regadenoson Alone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.022
	Estimation Comments

6. Secondary Outcome

Title	Proportion of Participants With Agreement in the Summed Difference Score (SDS) Between First and Second Stress Scans
Description	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.
Time Frame	Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	REG APEX: MPI 2 SDS 0-6	REG APEX: MPI 2 7-13	REG APEX: MPI 2 SDS ≥ 14	REG Alone: MPI 2 SDS 0-6	REG Alone: MPI 2 SDS 7-13	REG Alone: MPI 2 SDS ≥ 14
Arm/Group Description	Participants in the Regadenoson After Peak Exercise (APEX) group who had an SDS from 0 to 6 on their second stress scan.	Participants in the Regadenoson After Peak Exercise (REG APEX) group who had an SDS from 7 to 13 on their second stress scan.	Participants in the Regadenoson After Peak Exercise (REG APEX) group who had an SDS ≥ 14 on their second stress scan.	Participants in the Regadenoson (REG) Alone group who had an SDS from 0 to 6 on their second stress scan.	Participants in the Regadenoson (REG) Alone group who had an SDS from 7 to 13 on their second stress scan.	Participants in the Regadenoson (REG) Alone group who had an SDS ≥ 14 on their second stress scan.
Measure Participants	538	538	538	535	535	535
MPI 1 SDS 0-6	531 92.3%	4 0.7%	0 0%	527 NaN	3 NaN	0 NaN
MPI 1 SDS 7-13	0 0%	3 0.5%	0 0%	2 NaN	3 NaN	0 NaN
MPI 1 SDS ≥ 14	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN

7. Secondary Outcome

Title	Participants With Less, the Same, or More Reversible Perfusion Defects Shown by the First Stress Scan When Compared to the Second Stress Scan
Description	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.
Time Frame	Day 1 (stress MPI 1) and Day 2-15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Less Reversible Perfusion Defects	57 9.9%	49 8.6%
Same Number of Reversible Perfusion Defects	441 76.7%	459 81%
More Reversible Perfusion Defects	40 7%	27 4.8%

8. Secondary Outcome

Title	Overall Assessment of Image Quality
Description	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.
Time Frame	Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise	Regadenoson Alone
Arm/Group Description	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.	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.
Measure Participants	538	535
Rest MPI: Excellent	140 24.3%	157 27.7%
Rest MPI: Good	307 53.4%	308 54.3%
Rest MPI: Fair	91 15.8%	70 12.3%
Rest MPI: Poor	0 0%	0 0%
Stress MPI 1: Excellent	224 39%	211 37.2%
Stress MPI 1: Good	287 49.9%	291 51.3%
Stress MPI 1: Fair	27 4.7%	33 5.8%
Stress MPI 1: Poor	0 0%	0 0%
Stress MPI 2: Excellent	192 33.4%	205 36.2%
Stress MPI 2: Good	303 52.7%	293 51.7%
Stress MPI 2: Fair	43 7.5%	37 6.5%
Stress MPI 2: Poor	0 0%	0 0%

9. Secondary Outcome

Title	Target to Background Radiotracer Uptake Ratios From the First and Second Stress Scans
Description	Image quality was assessed through radiotracer uptake in the heart (target organ) compared to liver, gut and combined liver plus gut (background interference).
Time Frame	Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full analysis set participants who have planar images available for each scan

Arm/Group Title	Regadenoson After Peak Exercise: MPI 1	Regadenoson After Peak Exercise: MPI 2	Regadenoson Alone: MPI 1	Regadenoson Alone: MPI 2
Arm/Group Description	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.	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.	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.	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.
Measure Participants	514	525	518	523
Heart-to-Liver	1.05 (0.399)	0.94 (0.373)	0.96 (0.365)	0.95 (0.362)
Heart-to-Gut	1.12 (0.436)	0.99 (0.399)	1.05 (0.428)	0.99 (0.387)
Heart-to-(Liver/Gut)	1.02 (0.296)	0.90 (0.260)	0.94 (0.274)	0.91 (0.259)

10. Secondary Outcome

Title	Percentage of Scans With Subdiaphragmatic Interference
Description	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.
Time Frame	Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise: MPI 1	Regadenoson After Peak Exercise: MPI 2	Regadenoson Alone: MPI 1	Regadenoson Alone: MPI 2
Arm/Group Description	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.	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.	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.	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.
Measure Participants	284	284	270	270
None	0.4	0.0	0.0	0.0
Slight	71.8	63.7	68.1	67.4
Moderate	27.5	36.3	31.5	32.6
Severe	0.4	0.0	0.4	0.0

11. Secondary Outcome

Title	Percentage of Cardiac Segments Obscured by Subdiaphragmatic Activity
Description	The number of cardiac segments obscured by the sub-diaphragmatic activity by group by stress SPECT MPI scan and by reader is reported.
Time Frame	Day 1 (stress MPI 1) and Day - 15 (stress MPI 2)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Regadenoson After Peak Exercise: MPI 1	Regadenoson After Peak Exercise: MPI 2	Regadenoson Alone: MPI 1	Regadenoson Alone: MPI 2
Arm/Group Description	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.	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.	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.	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.
Measure Participants	538	538	535	535
Reader 1: Segment 1	0.0	0.0	0.0	0.0
Reader 1: Segment 2	0.0	0.0	0.0	0.0
Reader 1: Segment 3	0.0	0.0	0.0	0.0
Reader 1: Segment 4	33.6	37.2	34.2	37.4
Reader 1: Segment 5	9.7	8.4	7.9	7.7
Reader 1: Segment 6	0.0	0.0	0.0	0.0
Reader 1: Segment 7	0.0	0.0	0.0	0.0
Reader 1: Segment 8	0.0	0.0	0.0	0.0
Reader 1: Segment 9	0.0	0.0	0.0	0.0
Reader 1: Segment 10	31.6	35.5	32.3	36.3
Reader 1: Segment 11	9.5	8.2	7.5	7.5
Reader 1: Segment 12	0.0	0.0	0.0	0.0
Reader 1: Segment 13	0.0	0.0	0.0	0.0
Reader 1: Segment 14	0.0	0.0	0.0	0.0
Reader 1: Segment 15	1.7	0.9	2.4	2.1
Reader 1: Segment 16	0.0	0.0	0.2	0.2
Reader 1: Segment 17	0.0	0.0	0.0	0.0
Reader 2: Segment 1	0.0	0.0	0.0	0.0
Reader 2: Segment 2	0.0	0.0	0.2	0.0
Reader 2: Segment 3	0.0	0.0	0.2	0.6
Reader 2: Segment 4	34.4	35.1	32.5	32.5
Reader 2: Segment 5	1.1	0.4	0.7	0.7
Reader 2: Segment 6	0.0	0.0	0.0	0.0
Reader 2: Segment 7	0.0	0.0	0.0	0.0
Reader 2: Segment 8	0.0	0.2	0.0	0.0
Reader 2: Segment 9	0.0	0.0	0.4	0.4
Reader 2: Segment 10	12.6	11.9	13.8	13.1
Reader 2: Segment 11	0.0	0.2	0.6	0.2
Reader 2: Segment 12	0.0	0.0	0.0	0.0
Reader 2: Segment 13	0.0	0.0	0.0	0.0
Reader 2: Segment 14	0.0	0.0	0.0	0.0
Reader 2: Segment 15	9.1	8.7	10.5	9.5
Reader 2: Segment 16	0.0	0.2	0.0	0.0
Reader 2: Segment 17	0.4	0.0	0.0	0.0
Reader 3: Segment 1	0.0	0.2	0.0	0.0
Reader 3: Segment 2	0.0	0.0	0.0	0.0
Reader 3: Segment 3	0.0	0.0	0.0	0.0
Reader 3: Segment 4	14.1	16.7	17.9	17.2
Reader 3: Segment 5	0.6	0.4	0.7	0.2
Reader 3: Segment 6	0.0	0.0	0.0	0.0
Reader 3: Segment 7	0.0	0.0	0.0	0.0
Reader 3: Segment 8	0.0	0.0	0.0	0.0
Reader 3: Segment 9	0.0	0.0	0.0	0.0
Reader 3: Segment 10	16.0	17.8	18.5	18.9
Reader 3: Segment 11	0.7	0.2	0.6	0.2
Reader 3: Segment 12	0.0	0.0	0.0	0.0
Reader 3: Segment 13	0.2	0.0	0.0	0.0
Reader 3: Segment 14	0.0	0.0	0.0	0.0
Reader 3: Segment 15	13.9	13.8	13.1	14.6
Reader 3: Segment 16	0.4	0.7	0.4	0.2
Reader 3: Segment 17	0.9	0.9	0.7	0.6

12. Secondary Outcome

Title	Number of Participants With Adverse Events Within 24 Hours After Administration of Regadenoson
Description	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.
Time Frame	Up to 24 hours after study drug administration for each stress MPI (Day 1 and Day 2-15)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set.

Arm/Group Title	Regadenoson After Peak Exercise: MPI 1	Regadenoson After Peak Exercise: MPI 2	Regadenoson Alone: MPI 1	Regadenoson Alone: MPI 2
Arm/Group Description	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.	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.	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.	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.
Measure Participants	575	544	567	548
Any adverse event	302 52.5%	317 55.9%	329 28.8%	323 NaN
Drug-related adverse event	291 50.6%	298 52.6%	319 27.9%	308 NaN
Deaths	0 0%	0 0%	0 0%	0 NaN
Serious adverse events	5 0.9%	2 0.4%	1 0.1%	1 NaN
Drug-related serious adverse events	2 0.3%	0 0%	0 0%	0 NaN
Adverse events leading to discontinuation	13 2.3%	0 0%	5 0.4%	1 NaN
Drug-related AEs leading to discontinuation	9 1.6%	0 0%	5 0.4%	0 NaN

Adverse Events

Time Frame	From the time of administration of regadenoson to within 24 hours of administration of regadenoson for each stress MPI.
Arm/Group Title	Regadenoson After Peak Exercise: MPI 1		Regadenoson After Peak Exercise: MPI 2		Regadenoson Alone: MPI 1		Regadenoson Alone: MPI 2
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Regadenoson After Peak Exercise: MPI 1		Regadenoson After Peak Exercise: MPI 2		Regadenoson Alone: MPI 1		Regadenoson Alone: MPI 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Regadenoson After Peak Exercise: MPI 1		Regadenoson After Peak Exercise: MPI 2		Regadenoson Alone: MPI 1		Regadenoson Alone: MPI 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/575 (0.9%)		2/544 (0.4%)		1/567 (0.2%)		1/548 (0.2%)
Cardiac disorders
Acute coronary syndrome	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Cardiac failure congestive	0/575 (0%)		0/544 (0%)		1/567 (0.2%)		0/548 (0%)
Myocardial infarction	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Myocardial ischaemia	1/575 (0.2%)		1/544 (0.2%)		0/567 (0%)		0/548 (0%)
Eye disorders
Vision blurred	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Gastrointestinal disorders
Pancreatitis	0/575 (0%)		1/544 (0.2%)		0/567 (0%)		0/548 (0%)
Investigations
Anticoagulation drug level below therapeutic	0/575 (0%)		0/544 (0%)		0/567 (0%)		1/548 (0.2%)
Hepatic enzyme abnormal	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Nervous system disorders
Dizziness	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Speech disorder	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Syncope	1/575 (0.2%)		0/544 (0%)		0/567 (0%)		0/548 (0%)
Other (Not Including Serious) Adverse Events
	Regadenoson After Peak Exercise: MPI 1		Regadenoson After Peak Exercise: MPI 2		Regadenoson Alone: MPI 1		Regadenoson Alone: MPI 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	277/575 (48.2%)		274/544 (50.4%)		307/567 (54.1%)		290/548 (52.9%)
Gastrointestinal disorders
Abdominal pain upper	31/575 (5.4%)		35/544 (6.4%)		35/567 (6.2%)		34/548 (6.2%)
Nausea	43/575 (7.5%)		44/544 (8.1%)		45/567 (7.9%)		41/548 (7.5%)
General disorders
Chest discomfort	37/575 (6.4%)		33/544 (6.1%)		54/567 (9.5%)		43/548 (7.8%)
Nervous system disorders
Dizziness	106/575 (18.4%)		75/544 (13.8%)		89/567 (15.7%)		81/548 (14.8%)
Headache	85/575 (14.8%)		108/544 (19.9%)		137/567 (24.2%)		118/548 (21.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	141/575 (24.5%)		125/544 (23%)		161/567 (28.4%)		152/548 (27.7%)
Vascular disorders
Flushing	47/575 (8.2%)		78/544 (14.3%)		79/567 (13.9%)		69/548 (12.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data or 18 months after data-lock, whichever is first. Sponsor must receive a site's manuscript at least 45 days prior to publication for review and comment. Sponsor may delay the publication for up to 60 days to seek patent protection.