Caffeine's Effect on Regadenoson Administration With Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI)

• Sponsor: Astellas Pharma Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00826280
• Collaborator: (none)
• Enrollment: 347
• Locations: 25
• Arms: 3
• Actual Duration (Months): 15.7
• Patients Per Site: 13.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Observe whether the administration of caffeine prior to regadenoson will affect the interpretation of test results in subjects with coronary artery disease (CAD) undergoing SPECT MPI

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease (CAD)	Drug: regadenoson; Drug: overencapsulated caffeine; Radiation: technetium; Drug: placebo	Phase 3

Detailed Description

All subjects will undergo rest and stress scans. Those subjects who qualify by demonstrating at least 1 reversible defect, will undergo a third scan. All stress scans will involve the injection of regadenoson as the pharmacologic stress agent. Prior to the third scan, the subject will be administered blinded capsules of placebo or caffeine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 347 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: A Phase 3b, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Caffeine Intake on Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI) in Subjects Administered Regadenoson
• Actual Study Start Date: Mar 24, 2009
• Actual Primary Completion Date: Jul 15, 2010
• Actual Study Completion Date: Jul 15, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo plus Regadenoson Two placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	Drug: regadenoson; IV; Other Names: Lexiscan CVT 3146 ; Radiation: technetium; IV; Other Names: sestamibi tetrafosmin ; Drug: placebo; oral
Experimental: Caffeine 200 mg plus Regadenoson One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Drug: regadenoson; IV; Other Names: Lexiscan CVT 3146 ; Drug: overencapsulated caffeine; oral; Radiation: technetium; IV; Other Names: sestamibi tetrafosmin
Experimental: Caffeine 400 mg plus Regadenoson Two 200 mg Caffeine capsules plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Drug: regadenoson; IV; Other Names: Lexiscan CVT 3146 ; Drug: overencapsulated caffeine; oral; Radiation: technetium; IV; Other Names: sestamibi tetrafosmin

Outcome Measures

Primary Outcome Measures

1. Change in Number of Reversible Defects [Day 3 and Day 5]

   Each segment of the 17-Segment Model was assessed for radiotracer uptake on a scale of 0 (normal uptake) to 4 (absent uptake). Segments were counted as having a reversible defect if the stress score was greater than the rest score and the stress score was ≥ 2. Change was calculated as the number of reversible defects using regadenoson with caffeine/placebo (Day 5) minus the number of reversible defects using regadenoson alone (Day 3).

Secondary Outcome Measures

1. Change in Summed Difference Score (SDS) Across All 17 Segments [Day 3 and Day 5]

   The Summed Difference Score was calculated as the difference in the Summed Stress Score across the 17 segments (scan run under stress condition) minus the Summed Rest Score across the 17 segments (scan run under rest conditions). Change in SDS was calculated as the SDS for regadenoson with caffeine/placebo stress scan (Day 5) minus the SDS for regadenoson only stress scan (Day 3). The full range of the SDS is -68 to 68, where 0 represents no change between Summed Stress Score and Summed Rest Score. A higher positive score indicates more severe coronary artery disease (CAD).

2. Change in Number of Reversible Defects Assessed by Computerized Quantitation [Day 3 and Day 5]

   Each segment of the 17-Segment Model was assessed for radiotracer uptake on a scale of 0 (normal uptake) to 4 (absent uptake). Segments were counted as having a reversible defect if the stress score was greater than the rest score and the stress score was ≥ 2. Change was calculated as the number of reversible defects using regadenoson with caffeine/placebo (Day 5) minus the number of reversible defects using regadenoson alone (Day 3).

3. Change in Summed Difference Score Across All 17 Segments Assessed by Computerized Quantitation [Day 3 and Day 5]

   The Summed Difference Score was calculated as the difference in the Summed Stress Score across the 17 segments (scan run under stress condition) minus the Summed Rest Score across the 17 segments (scan run under rest conditions). Change in SDS was calculated as the SDS for regadenoson with caffeine/placebo stress scan (Day 5) minus the SDS for regadenoson only stress scan (Day 3). The full range of the SDS is -68 to 68, where 0 represents no change between Summed Stress Score and Summed Rest Score. A higher positive score indicates more severe coronary artery disease (CAD).

4. Change From Baseline in Heart Rate [Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)]

   Baseline is the last non-missing measurement on or before first dose of regadenoson Change is calculated as the time point minus baseline.

5. Change From Baseline in Systolic Blood Pressure [Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)]

   Baseline is the last non-missing measurement on or before first dose of regadenoson. Change is calculated as the time point minus baseline.

6. Change From Baseline in Diastolic Blood Pressure [Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)]

   Baseline is the last non-missing measurement on or before first dose of regadenoson. Change is calculated as the time point minus baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject must have undergone a previous diagnostic study [e.g., SPECT, echocardiography, magnetic resonance imaging (MRI), etc.] for a clinical indication demonstrating evidence of reversible defects in ≥ 1 vascular segment, have had other stress testing within the past 3 months, or the subject's history suggests at least a 50% likelihood of CAD

• If the previous diagnostic study shows only 1 reversible defect and it is in segment 17, another reversible defect will need to be present

• Subject with CAD must have an intermediate/low-risk for immediate intervention

• Subject must ingest caffeinated food or beverages regularly (at least the equivalent of one cup of caffeinated coffee daily)

• Subject must agree to not ingest any caffeine or other foods containing methylxanthine at least 24 hours prior to each study visit

• Subject must agree to abstain from eating solid food or drinking liquids other than water for at least 30 minutes prior to each study visit and 30 minutes following each study visit

Exclusion Criteria:

• Subject with documented myocardial infarction (MI) ≤ 30 days prior to enrollment

• Subject with history of percutaneous coronary intervention (PCI) ≤ 4 weeks prior to enrollment

• Subject with history of coronary artery bypass graft (CABG) ≤ 8 weeks prior to enrollment

• Subject has prior history of heart transplantation

• Subject has unstable angina, known severe left main coronary artery stenosis, severe heart failure, uncontrolled arrhythmias, symptomatic hypotension or severe hypertension (systolic blood pressure < 90 or > 180 mmHg, respectively), or > 1st degree atrioventricular block in the absence of a functioning pacemaker

• Subject requires emergent cardiac medical intervention or catheterization

• Subject has a history of smoking, regardless of frequency, tobacco type or method of intake, or using any smoking cessation products, including but not limited to the nicotine patch or nicotine gum, within 3 months prior to first dose of regadenoson

• Subject is currently undergoing treatment with theophylline, or theophylline containing medications within 7 days prior to randomization (Day 3)

• Subject has a history of known or suspected bronchoconstrictive or bronchospastic lung disease [e.g., asthma, wheezing, chronic obstructive pulmonary disease (COPD), etc.]

• Subject has a history of diabetes associated with gastric disorders and/or emptying

• Subject has end stage renal disease (ESRD) with a GFR< 15mL/min or currently undergoing dialysis for ESRD

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35294
2		Huntsville	Alabama	United States	35801
3		La Mesa	California	United States	91942
4		Mission Viejo	California	United States	92691
5		Roseville	California	United States	95661
6		Sacramento	California	United States	95819
7		Santa Rosa	California	United States	95405
8		Hartford	Connecticut	United States	06102-5037
9		Newark	Delaware	United States	19173
10		Jacksonville	Florida	United States	32216
11		Miami	Florida	United States	33173
12		Tamarac	Florida	United States	33321
13		Aurora	Illinois	United States	60504
14		Overland Park	Kansas	United States	66209
15		Auburn	Maine	United States	04210
16		Pittsfield	Massachusetts	United States	01201
17		Detroit	Michigan	United States	48202
18		Ypsilanti	Michigan	United States	48197
19		Kansas City	Missouri	United States	64111
20		Albany	New York	United States	12205
21		Rochester	New York	United States	14642-8679
22		Columbus	Ohio	United States	43214
23		Philadelphia	Pennsylvania	United States	19102
24		Wyomissing	Pennsylvania	United States	19610
25		Knoxville	Tennessee	United States	37920

Sponsors and Collaborators

• Astellas Pharma Inc

Investigators

• Study Director: Use Central Contact, Astellas Pharma Global Development

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to results on Astellas Clinical Study Results website

Publications

None provided.

• Responsible Party: Astellas Pharma Inc
• ClinicalTrials.gov Identifier: NCT00826280
• Other Study ID Numbers: 3606-CL-3002
• First Posted: Jan 22, 2009
• Last Update Posted: Dec 18, 2017
• Last Verified: Nov 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Astellas Pharma Inc: pharmacologic stress; ischemia; coronary artery disease (CAD)
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Caffeine; Regadenoson

Study Results

Participant Flow

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Period Title: Overall Study
STARTED	114	116	117
Safety Analysis Set	113	116	116
Completed Treatment	66	71	72
COMPLETED	66	70	71
NOT COMPLETED	48	46	46

Baseline Characteristics

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson	Total
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Total of all reporting groups
Overall Participants	66	70	71	207
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.0 (9.99)	65.7 (11.11)	69.4 (8.23)	67.7 (9.91)
Sex: Female, Male (Count of Participants)
Female	11 16.7%	12 17.1%	20 28.2%	43 20.8%
Male	55 83.3%	58 82.9%	51 71.8%	164 79.2%
Race/Ethnicity, Customized (participants) [Number]
White	61 92.4%	63 90%	68 95.8%	192 92.8%
Black or African American	5 7.6%	5 7.1%	3 4.2%	13 6.3%
American Indian or Alaska Native	0 0%	1 1.4%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.4%	0 0%	1 0.5%

Outcome Measures

1. Primary Outcome

Title	Change in Number of Reversible Defects
Description	Each segment of the 17-Segment Model was assessed for radiotracer uptake on a scale of 0 (normal uptake) to 4 (absent uptake). Segments were counted as having a reversible defect if the stress score was greater than the rest score and the stress score was ≥ 2. Change was calculated as the number of reversible defects using regadenoson with caffeine/placebo (Day 5) minus the number of reversible defects using regadenoson alone (Day 3).
Time Frame	Day 3 and Day 5

Outcome Measure Data

Analysis Population Description

The number of participants analyzed represents Full Analysis Set (FAS), which included all randomized subjects with interpretable Myocardial Perfusion Imaging (MPI) scans. The number of participants per arm is consistent for all categories of the data table.

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	66	70	71
Baseline Stress Scan (Day 3)	0.67 (1.377)	1.01 (1.452)	1.00 (1.595)
Double-Blind Stress Scan (Day 5)	0.80 (1.511)	0.40 (0.907)	0.38 (0.962)
DoubleBlind - Baseline (Day 5 - Day 3)	0.12 (0.981)	-0.61 (1.097)	-0.62 (1.367)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-Value is from the primary analysis using ANCOVA.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9328
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change in Summed Difference Score (SDS) Across All 17 Segments
Description	The Summed Difference Score was calculated as the difference in the Summed Stress Score across the 17 segments (scan run under stress condition) minus the Summed Rest Score across the 17 segments (scan run under rest conditions). Change in SDS was calculated as the SDS for regadenoson with caffeine/placebo stress scan (Day 5) minus the SDS for regadenoson only stress scan (Day 3). The full range of the SDS is -68 to 68, where 0 represents no change between Summed Stress Score and Summed Rest Score. A higher positive score indicates more severe coronary artery disease (CAD).
Time Frame	Day 3 and Day 5

Outcome Measure Data

Analysis Population Description

The number of participants analyzed represents Full Analysis Set (FAS), which included all randomized subjects with interpretable MPI scans. The number of participants per arm is consistent for all categories of the data table.

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	66	70	71
Baseline Stress Scan (Day 3)	2.24 (3.013)	2.45 (2.909)	2.53 (3.086)
Double-Blind Stress Scan (Day 5)	2.36 (3.247)	1.42 (2.091)	1.27 (2.003)
DoubleBlind - Baseline (Day 5 - Day 3)	0.11 (2.871)	-1.03 (2.071)	-1.25 (2.664)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	P-Value is from the primary analysis using ANCOVA.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5902
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Change in Number of Reversible Defects Assessed by Computerized Quantitation
Description	Each segment of the 17-Segment Model was assessed for radiotracer uptake on a scale of 0 (normal uptake) to 4 (absent uptake). Segments were counted as having a reversible defect if the stress score was greater than the rest score and the stress score was ≥ 2. Change was calculated as the number of reversible defects using regadenoson with caffeine/placebo (Day 5) minus the number of reversible defects using regadenoson alone (Day 3).
Time Frame	Day 3 and Day 5

Outcome Measure Data

Analysis Population Description

The number of participants analyzed per arm represents Full Analysis Set (FAS), all randomized subjects with interpretable MPI scans. The number of participants included in the calculation for each visit is noted in the category titles, as "N".

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	66	70	71
Baseline Stress Scan (Day 3) [N=64; 69; 70]	1.47 (1.927)	2.00 (2.364)	2.19 (2.122)
Double-Blind Stress Scan (Day 5) [N=66; 70; 71]	1.74 (2.355)	1.46 (1.954)	1.42 (1.794)
DoubleBlind - Baseline (Day 5-Day 3)[N=64; 69; 70]	0.31 (1.622)	-0.59 (1.743)	-0.81 (1.812)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0037
	Comments	P-Value is from the primary analysis using ANCOVA.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5654
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change in Summed Difference Score Across All 17 Segments Assessed by Computerized Quantitation
Description	The Summed Difference Score was calculated as the difference in the Summed Stress Score across the 17 segments (scan run under stress condition) minus the Summed Rest Score across the 17 segments (scan run under rest conditions). Change in SDS was calculated as the SDS for regadenoson with caffeine/placebo stress scan (Day 5) minus the SDS for regadenoson only stress scan (Day 3). The full range of the SDS is -68 to 68, where 0 represents no change between Summed Stress Score and Summed Rest Score. A higher positive score indicates more severe coronary artery disease (CAD).
Time Frame	Day 3 and Day 5

Outcome Measure Data

Analysis Population Description

The number of participants analyzed per arm represents Full Analysis Set (FAS), all randomized subjects with interpretable MPI scans. The number of participants included in the calculation for each visit is noted in the category titles, as "N".

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	66	70	71
Baseline Stress Scan (Day 3) [N=64; 69; 70]	3.34 (4.383)	4.46 (4.604)	4.29 (4.314)
Double-Blind Stress Scan (Day 5) [N=66; 70; 71]	4.41 (4.874)	3.10 (4.737)	2.46 (3.601)
DoubleBlind - Baseline (Day 5-Day 3)[N=64; 69; 70]	1.02 (3.364)	-1.45 (3.890)	-1.84 (3.658)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-Value is from the primary analysis using ANCOVA.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 200 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Caffeine 200 mg Plus Regadenoson, Caffeine 400 mg Plus Regadenoson
	Comments	P-Value applies to 'Double-Blind - Baseline (Day 5 - Day 3)'.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.4246
	Comments	The unadjusted P-Values for pairwise differences should be used for interpretation only if the treatment effect's P-Value ≤ 0.05.
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change From Baseline in Heart Rate
Description	Baseline is the last non-missing measurement on or before first dose of regadenoson Change is calculated as the time point minus baseline.
Time Frame	Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)

Outcome Measure Data

Analysis Population Description

The number of participants analyzed per arm represents Safety Analysis Set (SAF) all randomized patients who received at least one dose of regadenoson. The number of participants included in the calculation for each visit is noted in the category titles, as "N".

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	113	116	116
Baseline [N=113; 116; 116]	66.0	62.0	64.0
Change at Day 5 (- 3 min) [N=67; 70; 71]	-2.0	-1.0	-2.0
Change at Day 5 (+3 min) [N=67; 70; 72]	9.0	5.0	0.0
Change at Day 5 (+15 min) [N=66; 72; 72]	4.0	1.0	-1.0

6. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure
Description	Baseline is the last non-missing measurement on or before first dose of regadenoson. Change is calculated as the time point minus baseline.
Time Frame	Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)

Outcome Measure Data

Analysis Population Description

The number of participants analyzed per arm represents Safety Analysis Set (SAF) all randomized patients who received at least one dose of regadenoson. The number of participants included in the calculation for each visit is noted in the category titles, as "N".

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	113	116	116
Baseline [N=113; 116; 116]	135.0	131.0	135.0
Change at Day 5 (- 3 min) [N=67;70;71]	0.0	12.0	11.0
Change at Day 5 (+3 min) [N=67; 70; 72]	0.0	8.0	7.5
Change at Day 5 (+15 min) [N=66; 72; 72]	-2.0	8.0	5.0

7. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure
Description	Baseline is the last non-missing measurement on or before first dose of regadenoson. Change is calculated as the time point minus baseline.
Time Frame	Baseline, Day 5 (-3 min), Day 5 (+3 min), Day 5 (+15 min)

Outcome Measure Data

Analysis Population Description

The number of participants analyzed per arm represents Safety Analysis Set (SAF) all randomized patients who received at least one dose of regadenoson. The number of participants included in the calculation for each visit is noted in the category titles, as "N".

Arm/Group Title	Placebo Plus Regadenoson	Caffeine 200 mg Plus Regadenoson	Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection	One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection	Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
Measure Participants	113	116	116
Baseline [N= 113; 116;116]	78.0	74.0	73.0
Change at Day 5 (- 3 min) [N=67; 70; 71]	0.0	4.0	6.0
Change at Day 5 (+ 3 min) [N=67; 70; 72]	-1.0	4.0	3.0
Change at Day 5 (+15 min) [N=66; 72; 72]	-2.0	3.0	4.0

Adverse Events

Time Frame	Beginning of Day 3 through the Day 6 visit. All Serious Adverse Events occurring until 30 days after dosing were to be reported.
Adverse Event Reporting Description	Any untoward medical occurrence that occurred at the beginning of day 3 (Baseline Stress Scan) through the day 6 visit (considered "treatment- emergent") was recorded as an Adverse Event. Within a system organ class subjects may have reported more than one type of Adverse Event.
Arm/Group Title	Placebo Plus Regadenoson		Caffeine 200 mg Plus Regadenoson		Caffeine 400 mg Plus Regadenoson
Arm/Group Description	Two Placebo capsules plus 0.4 mg regadenoson per 5mL intravenous (IV) bolus injection		One 200 mg Caffeine capsule and one placebo capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection		Two 200 mg Caffeine capsule plus 0.4 mg regadenoson per 5mL intravenous bolus injection
All Cause Mortality
	Placebo Plus Regadenoson		Caffeine 200 mg Plus Regadenoson		Caffeine 400 mg Plus Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Plus Regadenoson		Caffeine 200 mg Plus Regadenoson		Caffeine 400 mg Plus Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/113 (0.9%)		2/116 (1.7%)		2/116 (1.7%)
Cardiac disorders
Angina pectoris	1/113 (0.9%)		1/116 (0.9%)		0/116 (0%)
Acute coronary syndrome	0/113 (0%)		0/116 (0%)		1/116 (0.9%)
Myocardial infraction	0/113 (0%)		1/116 (0.9%)		0/116 (0%)
Acute myocardial infraction	0/113 (0%)		0/116 (0%)		1/116 (0.9%)
Renal failure acute	0/113 (0%)		0/116 (0%)		1/116 (0.9%)
Other (Not Including Serious) Adverse Events
	Placebo Plus Regadenoson		Caffeine 200 mg Plus Regadenoson		Caffeine 400 mg Plus Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/113 (72.6%)		89/116 (76.7%)		80/116 (69%)
Gastrointestinal disorders
Abdominal discomfort	6/113 (5.3%)		3/116 (2.6%)		5/116 (4.3%)
Abdominal pain upper	6/113 (5.3%)		4/116 (3.4%)		5/116 (4.3%)
Nausea	13/113 (11.5%)		16/116 (13.8%)		10/116 (8.6%)
Stomach discomfort	7/113 (6.2%)		4/116 (3.4%)		4/116 (3.4%)
Feeling hot	3/113 (2.7%)		5/116 (4.3%)		6/116 (5.2%)
General disorders
Chest discomfort	22/113 (19.5%)		25/116 (21.6%)		19/116 (16.4%)
Chest pain	8/113 (7.1%)		1/116 (0.9%)		2/116 (1.7%)
Nervous system disorders
Dizziness	22/113 (19.5%)		25/116 (21.6%)		18/116 (15.5%)
Dysgeusia	4/113 (3.5%)		11/116 (9.5%)		5/116 (4.3%)
Headache	36/113 (31.9%)		37/116 (31.9%)		38/116 (32.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	43/113 (38.1%)		47/116 (40.5%)		34/116 (29.3%)
Vascular disorders
Flushing	27/113 (23.9%)		29/116 (25%)		27/116 (23.3%)

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