A Study of Regadenoson in Subjects Undergoing Stress Myocardial Perfusion Imaging (MPI) Using Multidetector Computed Tomography (MDCT) Compared to Single Photon Emission Computed Tomography (SPECT)

All participants will be randomized to one of two imaging sequences: rest/stress SPECT on Day 1 followed by stress/rest MDCT on Day 2 or stress/rest MDCT on Day 1 followed by rest/stress SPECT on Day 2. All stress scans will involve the injection of regadenoson as the pharmacologic stress agent.

• regadenoson (Drug), also known as CVT 3146, Lexiscan: Administered by intravenous bolus.
• technetium Tc99m sestamibi /technetium Tc99m tetrafosmin (Radiation), also known as Cardiolite, Myoview: Administered by intravenous infusion
• Contrast (Radiation): Administered by intravenous infusion.
• Single Photon Emission Computed Tomography (Procedure): Procedure/Surgery
• Multidetector Computed Tomography (Procedure): Procedure/Surgery

Primary outcomes

• Number of Participants With Reversible Defects [Day 1 and Day 2]: The number of reversible defects categorized into absence or presence of ischemia (0-1 versus ≥2), as assessed by the central imaging laboratory for both SPECT and MDCT. The 17-segment model for standardized myocardial segmentation was used for myocardial perfusion readings for SPECT and MDCT. 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/radiotracer uptake -2: moderately reduced contrast/radiotracer uptake -3: severely reduced contrast/radiotracer uptake -4: absent contrast/radiotracer uptake. The median score from the 3 blinded readers for each segment was used. 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. A participant was classified as ischemic in the presence of 2 or more segments with reversible defects, excluding segment 17.

Secondary outcomes

• Overall Image Quality of Scans by Modality and Reviewer [Day 1 and Day 2]: Overall image quality was assessed by three independent blinded readers for each modality (single photon emission computed tomography (SPECT) and multidetector computed tomography (MDCT)). Image quality was rated on a 4-point scale as either excellent, good, fair or poor at rest using SPECT and MDCT and under stress using regadenoson SPECT and regadenoson stress computed tomography perfusion (CTP).
• Number of Participants With Reversible Defects in the Left Anterior Descending Coronary Artery (LAD) [Day 1 and Day 2]: The number of reversible defects in the LAD categorized into absence or presence of ischemia (0-1 versus ≥2), as assessed by the central imaging laboratory for both SPECT and MDCT. The 17-segment model for standardized myocardial segmentation was used for myocardial perfusion readings for SPECT and MDCT. 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/radiotracer uptake -2: moderately reduced contrast/radiotracer uptake -3: severely reduced contrast/radiotracer uptake -4: absent contrast/radiotracer uptake. The median score from 3 blinded readers for each segment was used. 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. A participant was classified as ischemic in the presence of ≥ 2 segments with reversible defects, excluding segment 17.
• Number of Participants With Reversible Defects in the Right Coronary Artery (RCA) [Day 1 and Day 2]: The number of reversible defects in the RCA categorized into absence or presence of ischemia (0-1 versus ≥2), as assessed by the central imaging laboratory for both SPECT and MDCT. The 17-segment model for standardized myocardial segmentation was used for myocardial perfusion readings for SPECT and MDCT. 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/radiotracer uptake -2: moderately reduced contrast/radiotracer uptake -3: severely reduced contrast/radiotracer uptake -4: absent contrast/radiotracer uptake. The median score from 3 blinded readers for each segment was used. 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. A participant was classified as ischemic in the presence of ≥ 2 segments with reversible defects, excluding segment 17.
• Number of Participants With Reversible Defects in the Left Circumflex Coronary Artery (LCX) [Day 1 and Day 2]: The number of reversible defects in the LCX categorized into absence or presence of ischemia (0-1 versus ≥2), as assessed by the central imaging laboratory for both SPECT and MDCT. The 17-segment model for standardized myocardial segmentation was used for myocardial perfusion readings for SPECT and MDCT. 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/radiotracer uptake -2: moderately reduced contrast/radiotracer uptake -3: severely reduced contrast/radiotracer uptake -4: absent contrast/radiotracer uptake. The median score from 3 blinded readers for each segment was used. 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. A participant was classified as ischemic in the presence of ≥ 2 segments with reversible defects, excluding segment 17.
• Number of Participants With Fixed Defects [Day 1 and Day 2]: Using the 17-segment scoring system, a segment scored above 1 (i.e., 2 to 4) and equal at rest and stress was counted as having a fixed defect. 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/radiotracer uptake -2: moderately reduced contrast/radiotracer uptake -3: severely reduced contrast/radiotracer uptake -4: absent contrast/radiotracer uptake.
• Percentage of Participants With Two or More Ischemic Segments on SPECT, But Less on CT [Day 1 and Day 2]: Using SPECT as the reference standard, the false negative percentage was calculated as the percentage of participants with two or more ischemic segments on SPECT, but less on CT.

Sex: All, ages: 45 Years to any

Inclusion Criteria:

* Male subjects must be ≥ 45 years of age
* Female subjects must be ≥ 50 years of age
* Subject has met at least one of the following three criteria:

  * has a suspected (clinical impression) or known diagnosis of coronary artery disease (CAD) with typical angina that has been referred from nuclear cardiology lab schedule or cardiac computed tomography (CT) schedule
  * has stable symptoms with possible elective catheterization procedure scheduled and where further imaging may be beneficial;
  * has known CAD from a previous invasive coronary angiography (ICA) performed more than 12 weeks prior to screening who now present with new cardiac symptoms
* Subject has been referred for a clinically indicated myocardial perfusion imaging procedure or Cardiac CT procedure for suspected moderate or high risk CAD
* Subject must abstain from eating and drinking 30 minutes prior and 30 minutes post study drug administration
* Subject must abstain from smoking 3 hours prior and 8 hours post study drug administration
* Subject must abstain from any intake of methylxanthine-containing foods and beverages within 12 hours prior to Day 1 visit through the Day 3 Follow-Up Visit, as these foods may alter regadenoson effects. Subject is able to safely abstain from theophylline use for 12 hours prior to study drug administration

Exclusion Criteria:

* Subject is concurrently participating in another drug study or has received an investigational drug within 30 days prior to Screening
* Subject has a history of a clinically significant illness (other than CAD), medical condition, or laboratory abnormality, which would preclude participation in the study
* Subject has renal dysfunction demonstrated by a glomerular filtration rate (GFR) < 45 mL/min (calculated using Cockroft-Gault formula Note: Subjects with a GFR 45-60 mL/min will undergo a hydration procedure
* Female subject who is pregnant, lactating or of childbearing potential that refuses to use a medically acceptable form of contraception until the Telephone Follow up Visit is complete
* Female subject has a positive pregnancy test prior to randomization
* Subject has a history of second or third degree heart block or sinus node dysfunction unless the subject has a functioning pacemaker
* Subject has symptomatic hypotension (temporary and reversible conditions that no longer exist are allowed)
* Subject is allergic or intolerant to aminophylline, nitroglycerin or metoprolol
* Subject is allergic or intolerant to regadenoson or any of its excipients
* Subject is unable or unwilling to comply with the procedure schedule
* Subject has previously enrolled in this study or was enrolled in another regadenoson study sponsored by Astellas
* Subject has atrial fibrillation or significant arrhythmias which may result in decreased image quality for the imaging studies (CT and SPECT)
* Subject has high heart rate (> 65 beats per minute) and contra-indications to administer beta-blockers (severe chronic obstructive pulmonary disease (COPD) or asthma, second and third degree atrioventricular block)

Participant flow

Outcome results

• Number of Participants With Reversible Defects (Primary), Number, participants: CTP: 0 - 1 Reversible Defects 84; CTP: ≥ 2 Reversible Defects 16; CTP: All Reversible Defects 100
• Overall Image Quality of Scans by Modality and Reviewer (Secondary), Number, participants: SPECT: Reviewer 1 89; SPECT: Reviewer 2 25; SPECT: Reviewer 3 83; MDCT: Reviewer 1 30; MDCT: Reviewer 2 40; MDCT: Reviewer 3 56
• Number of Participants With Reversible Defects in the Left Anterior Descending Coronary Artery (LAD) (Secondary), Number, participants: CTP: 0 - 1 Reversible Defects 90; CTP: ≥ 2 Reversible Defects 11; CTP: All Reversible Defects 101
• Number of Participants With Reversible Defects in the Right Coronary Artery (RCA) (Secondary), Number, participants: CTP: 0 - 1 Reversible Defects 92; CTP: ≥ 2 Reversible Defects 5; CTP: All Reversible Defects 97
• Number of Participants With Reversible Defects in the Left Circumflex Coronary Artery (LCX) (Secondary), Number, participants: CTP: 0 - 1 Reversible Defects 90; CTP: ≥ 2 Reversible Defects 9; CTP: All Reversible Defects 99
• Number of Participants With Fixed Defects (Secondary), Number, participants: CTP: 0 Fixed Defects 92; CTP: ≥ 1 Fixed Defects 5; CTP: All Fixed Defects 97
• Percentage of Participants With Two or More Ischemic Segments on SPECT, But Less on CT (Secondary), Number, percentage of participants: SPECT + MDCT 10

Adverse events

Time frame: Treatment-emergent adverse events (TEAEs) were defined as adverse events observed from the time of administration of regadenoson to 24 hours after last study drug administration within each modality, i.e. from Day 1 to Day 3.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Company makes no warranties or representations of any kind as to the posting, expressed or implied, including warranties of merchantability and fitness for a particular purpose, and shall not be liable for any damages.

• Results publication: Cury RC, Kitt TM, Feaheny K, Akin J, George RT. Regadenoson-stress myocardial CT perfusion and single-photon emission CT: rationale, design, and acquisition methods of a prospective, multicenter, multivendor comparison. J Cardiovasc Comput Tomogr. 2014 Jan-Feb;8(1):2-12. doi: 10.1016/j.jcct.2013.09.004. Epub 2013 Oct 18. PMID 24314823

• Senior Medical Director, Study director, Astellas Pharma Global Development