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) (EXERRT)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
ClinicalTrials.gov Identifier:
NCT01618669
First received: May 29, 2012
Last updated: January 7, 2016
Last verified: January 2016

May 29, 2012
January 7, 2016
June 2012
December 2014   (final data collection date for primary outcome measure)
Proportion of Participants With Majority Reader Self-agreement in Ischemia Assessment Between First and Second Stress Scans [ Time Frame: Day 1 (rest scan and first stress scan) and Day 2 -15 (second stress scan) ] [ Designated as safety issue: No ]

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.

Median count of the number of segments with reversible defects categorized as absence (0-1) or presence of ischemia (≥2) [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
Non-inferiority will be provided by a confidence interval on the difference in agreement rates (agreement rate for SPECT images at Visit 2 and Visit 3 in Regadenoson After Peak Exercise arm minus agreement rate for SPECT images at Visit 2 and Visit 3 in Regadenoson Alone arm). Measure of agreement is average rate of agreement for absence or presence of ischemia based on median count between the successive scan images. The median count is across three blinded independent expert readers.
Complete list of historical versions of study NCT01618669 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With Treatment-emergent Clinically Significant Cardiac Events [ Time Frame: Within 1 hour for ECG events and up to 24 hours for adverse events after administration of regadenoson ] [ Designated as safety issue: Yes ]

    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.
  • Proportion of Participants With Agreement in the Assessment of Absence or Presence of Ischemia Between First and Second Stress Scans [ Time Frame: Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2) ] [ Designated as safety issue: No ]
    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.
  • Proportion of Participants With Agreement in the Assessment of Reversible Defects in 3 Categories of Ischemia Between First and Second Stress Scans [ Time Frame: Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) ] [ Designated as safety issue: No ]
    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.
  • Proportion of Participants With Agreement in the Summed Stress Score (SSS) Between First and Second Stress Scans [ Time Frame: Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) ] [ Designated as safety issue: No ]

    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.

  • Proportion of Participants With Agreement in the Summed Difference Score (SDS) Between First and Second Stress Scans [ Time Frame: Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2) ] [ Designated as safety issue: No ]

    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.

  • Participants With Less, the Same, or More Reversible Perfusion Defects Shown by the First Stress Scan When Compared to the Second Stress Scan [ Time Frame: Day 1 (stress MPI 1) and Day 2-15 (stress MPI 2) ] [ Designated as safety issue: No ]
    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.
  • Overall Assessment of Image Quality [ Time Frame: Day 1 (rest MPI and stress MPI 1) and Day 2 - 15 (stress MPI 2) ] [ Designated as safety issue: No ]
    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.
  • Target to Background Radiotracer Uptake Ratios From the First and Second Stress Scans [ Time Frame: Day 1 (stress MPI 1) and Day 2 - 15 (stress MPI 2) ] [ Designated as safety issue: No ]
    Image quality was assessed through radiotracer uptake in the heart (target organ) compared to liver, gut and combined liver plus gut (background interference).
  • Percentage of Scans With Subdiaphragmatic Interference [ Time Frame: Day 1 (stress MPI 1) and Day 2 -15 (stress MPI 2) ] [ Designated as safety issue: No ]
    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.
  • Percentage of Cardiac Segments Obscured by Subdiaphragmatic Activity [ Time Frame: Day 1 (stress MPI 1) and Day - 15 (stress MPI 2) ] [ Designated as safety issue: No ]
    The number of cardiac segments obscured by the sub-diaphragmatic activity by group by stress SPECT MPI scan and by reader is reported.
  • Number of Participants With Adverse Events Within 24 Hours After Administration of Regadenoson [ Time Frame: Up to 24 hours after study drug administration for each stress MPI (Day 1 and Day 2-15) ] [ Designated as safety issue: Yes ]

    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.

  • Agreement rates between SPECT imaging with regadenoson following inadequate exercise stress testing and SPECT imaging with regadenoson alone using 3 categories for ischemia [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
    Ischemia categories are 0-1, 2-4, ≥ 5 reversible segments
  • Agreement of image pairs with regard to reader summed difference score (SDS) and summed stress score (SSS) and a paired (side by side) comparison of ischemic extent [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
    Image pairs include regadenoson following inadequate exercise versus regadenoson and regadenoson versus regadenoson
  • Overall assessment of image quality between scans obtained with regadenoson myocardial perfusion imaging (MPI) and regadenoson exercise MPI [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
    Image quality is defined by the independent readers as excellent, good, fair or poor
  • Target (heart) to background radiotracer ratio of the heart to liver and heart to gut between regadenoson MPI and regadenoson exercise MPI [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
  • Target (heart) to background radiotracer ratio of the combined background ratio of gut and liver (mean of gut and liver) between regadenoson MPI and regadenoson exercise MPI [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
  • Sub diaphragmatic radiotracer activity interference with cardiac image quality using a 0-4 scale between regadenoson MPI and regadenoson exercise MPI [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
    The scores are defined as: 0=normal radiotracer uptake, 1=slightly reduced radiotracer uptake, 2=moderately reduced radiotracer uptake, 3=severely reduced radiotracer uptake and 4=absent radiotracer uptake
  • Cardiac segments obscured by the sub diaphragmatic activity between regadenoson MPI and regadenoson exercise MPI [ Time Frame: Visit 2 (Day 1) and Visit 3 (Day 2 up to Day 15) ] [ Designated as safety issue: No ]
  • Percentage of subjects experiencing one or more treatment-emergent adverse events (TEAE) within 2 hours after administration of regadenoson [ Time Frame: up to 2 hours after study drug ] [ Designated as safety issue: Yes ]
  • Percentage of subjects experiencing one or more TEAEs within 24 hours after administration of regadenoson [ Time Frame: up to 24 hours after study drug ] [ Designated as safety issue: Yes ]
  • Percentage of subjects who experience one or more clinically significant cardiac events found on electrocardiogram (ECG) [ Time Frame: within 1 hour after administration of regadenoson ] [ Designated as safety issue: Yes ]
    The significant cardiac events are: number of ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation) ST-T depression (>2 mm); ST-T elevation (>1 mm), incidence of atrioventricular (AV) block; sinus arrest > 3 seconds in duration and/or percentage of subjects experiencing adverse events of acute coronary syndrom (unstable angina and/or acute myocardial infarction)
  • Changes in heart rate (HR) from baseline to each scheduled observation and to highest observed value within 1 hour after regadenoson administration as assessed by ECG [ Time Frame: Baseline and up to 1 hour after study drug administration ] [ Designated as safety issue: Yes ]
    Baseline is on Visit 2 (Day 1)
  • Percent of subjects with HR >100 bpm [ Time Frame: Baseline and post baseline (Visit 2 and Visit 3) ] [ Designated as safety issue: Yes ]
    Baseline is on Visit 2 (Day 1). Visit 3 is between Day 2 and Day 15
  • Percent of subjects with HR increase > 40 bpm [ Time Frame: Baseline and post baseline (Visit 2 and Visit 3) ] [ Designated as safety issue: Yes ]
    Baseline is on Visit 2 (Day 1). Visit 3 is between Day 2 and Day 15
  • Proportion of subjects with vital sign changes [ Time Frame: Baseline and post baseline (Visit 2 and Visit 3) ] [ Designated as safety issue: Yes ]
    Baseline is on Visit 2 (Day 1). Visit 3 is between Day 2 and Day 15. Vital sign changes defined as a systolic blood pressure (SBP) decrease of 35 mmHg or more, a SBP less than 90 mmHg or more, SBP ≥ 200 mmHg, SBP ≥ 180 mmHg with an increase of 20 mmHg, an increase in SBP of ≥ 50 mmHg, diastolic blood pressure < 50 mmHg, decrease > 25 mmHg, ≥ 115 mmHg, or increase ≥ 30 mmHg
Not Provided
Not Provided
 
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)
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)
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.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Coronary Artery Disease (CAD)
  • Drug: Regadenoson
    Administered as an intravenous (IV) bolus
    Other Names:
    • Lexiscan
    • CVT3146
  • Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)
  • 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.
    Interventions:
    • Drug: Regadenoson
    • 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.
    Interventions:
    • Drug: Regadenoson
    • Procedure: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1147
December 2014
December 2014   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Argentina,   Peru,   Puerto Rico
 
NCT01618669
3606-CL-3004
No
Undecided
Not Provided
Astellas Pharma Global Development, Inc.
Astellas Pharma Global Development, Inc.
Not Provided
Study Director: Senior Medical Director Astellas Pharma Global Development, Inc.
Astellas Pharma Inc
January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP