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)

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.

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.

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.

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.

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.

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.

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.

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.

Image quality was assessed through radiotracer uptake in the heart (target organ) compared to liver, gut and combined liver plus gut (background 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.

The number of cardiac segments obscured by the sub-diaphragmatic activity by group by stress SPECT MPI scan and by reader is reported.

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.