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)

Study Overview
=================
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.

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)

Conditions
-----------------
Coronary Artery Disease (CAD)

Intervention / Treatment
-----------------
* Drug: Regadenoson
* Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects referred for an exercise or pharmacologic stress test SPECT MPI procedure for the evaluation of coronary artery disease (CAD) are eligible for study participation. Subjects referred for pharmacologic stress should have a reasonable potential of attempting exercise stress. Subject must have one of the following: a. Past ischemia on any prior imaging stress test without invasive intervention on the artery subtending this territory b. Subject with known CAD who have symptoms similar to previous ischemic symptoms, or recent onset of symptoms or recently worsened symptoms suggestive of ischemia c. Diamond Forrester estimated pretest probability of CAD of ≥ 50% d. History of most recent coronary artery bypass surgery or most recent percutaneous coronary intervention (PCI) > 10 years (patients who are > 30 days but less than 10 years post coronary artery bypass graft (CABG) or PCI can be included if they meet criteria a, b, or e) e. Previously demonstrated 100% occlusion by invasive coronary or computed tomography (CT) angiography without successful intervening revascularization as these foods may alter regadenoson effects Exclusion Criteria: Subject has a clinically significant illness, medical condition, or laboratory abnormality Female subject who is pregnant or lactating Subject is on dialysis for end stage renal disease or has a history of glomerular filtration rate (GFR) < 15 mL/min (calculated using MDRD [Modification of Diet in Renal Disease] formula) Subject has a history of coronary revascularization by either PCI or CABG within 1 month prior to the rest myocardial perfusion imaging (MPI) Subject has a pacemaker or an implantable cardioverter defibrillator (ICD) Subject has a history of acute myocardial infarction (MI) or high risk unstable angina within 30 days prior to the rest MPI or has had cardiac transplantation Subject has uncontrolled hypertension at any point on Visit 2 prior to exercise testing (i.e., systolic blood pressure (SBP) ≥ 180 or diastolic blood pressure (DBP) ≥ 95 mmHg on two consecutive measurements while at rest). Subject has severe aortic stenosis or hypertrophic cardiomyopathy with obstruction or has decompensated congestive heart failure Subject has a history of severe respiratory disease including: asthma, chronic obstructive pulmonary disease (COPD) or other bronchospastic reactive airway disease or who is on 24-hour continuous oxygen

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regadenoson After Peak Exercise<br>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<br>* Administered as an intravenous (IV) bolus<br>* Other names: CVT3146;Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)<br> <br> |
| Active Comparator: Regadenoson Alone<br>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<br>* Administered as an intravenous (IV) bolus<br>* Other names: CVT3146;Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-emergent Clinically Significant Cardiac Events | 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. | Within 1 hour for ECG events and up to 24 hours for adverse events after administration of regadenoson | 
| Proportion of Participants With Agreement in the Assessment of Absence or Presence of Ischemia Between First and Second Stress Scans | 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. | Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2) | 
| Proportion of Participants With Agreement in the Assessment of Reversible Defects in 3 Categories of Ischemia Between First and Second Stress Scans | 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. | Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) | 
| Proportion of Participants With Agreement in the Summed Stress Score (SSS) Between First and Second Stress Scans | 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. | Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) | 
| Proportion of Participants With Agreement in the Summed Difference Score (SDS) Between First and Second Stress Scans | 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. | Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2) | 
| Participants With Less, the Same, or More Reversible Perfusion Defects Shown by the First Stress Scan When Compared to the Second Stress Scan | 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. | Day 1 (stress MPI 1) and Day 2-15 (stress MPI 2) | 
| Overall Assessment of Image Quality | 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. | Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2) | 
| Target to Background Radiotracer Uptake Ratios From the First and Second Stress Scans | Image quality was assessed through radiotracer uptake in the heart (target organ) compared to liver, gut and combined liver plus gut (background interference). | Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) | 
| Percentage of Scans With Subdiaphragmatic Interference | 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. | Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2) | 
| Percentage of Cardiac Segments Obscured by Subdiaphragmatic Activity | The number of cardiac segments obscured by the sub-diaphragmatic activity by group by stress SPECT MPI scan and by reader is reported. | Day 1 (stress MPI 1) and Day - 15 (stress MPI 2) | 
| Number of Participants With Adverse Events Within 24 Hours After Administration of Regadenoson | 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. | Up to 24 hours after study drug administration for each stress MPI (Day 1 and Day 2-15) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Coronary Artery Disease (CAD), regadenoson, pharmacologic stress