Assessing myocardial perfusion in suspected coronary artery disease: rationale and design of the second phase 3, open-label multi-center study of flurpiridaz (F-18) injection for positron emission tomography (PET) imaging

Abstract

Background

Positron emission tomography (PET) myocardial perfusion imaging (MPI) with the novel radiopharmaceutical Fluorine-18 Flurpiridaz has been shown in Phase 1, 2, and first Phase 3 clinical studies to be safe and effective in diagnosing coronary artery disease (CAD). We describe the methodology of the second FDA-mandated phase 3 prospective, open-label, international, multi-center trial of F-18 Flurpiridaz PET MPI.

Methods

The primary study end point is to assess the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD [≥ 50% by quantitative invasive coronary angiography (ICA)] in patients with suspected CAD. The secondary endpoints are to evaluate the diagnostic efficacy of F-18 Flurpiridaz PET MPI compared to Tc-99 m-labeled SPECT MPI in the detection of CAD in all patients and in the following subgroups: (1) females; (2) patients with body mass index ≥ 30 kg/m2; and (3) diabetic patients. This trial’s design differs from the first phase 3 trial in that (1) comparison to SPECT is now a secondary end point; (2) patients with known CAD are excluded; and (3) both SPECT and PET MPI are performed before ICA.

Conclusions

This second phase 3 study will provide additional evidence on the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD.

Trial Registration Number:

NCT03354273

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Figure 1

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Acknowledgments

This study was sponsored by GE Healthcare.

Disclosures

Dr. Bourque performs consulting for General Electric Inc. and Pfizer Inc. Dr. Hanson is supported by the National Institute of Biomedical Imaging and Bioengineering grant 5T32EB003841. Dr. Bax has received unrestricted research grants from Abbott, Bayer, Biotronik, Boston Scientific, Edwards Lifescience, GE Healthcare, and Medtronic. Dr. Bax receives speaker fees from Abbott. Dr. Beanlands has received research support and honoraria from Lantheus Medical Imaging, Jubilant DraxImage, and GE Healthcare.

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Correspondence to Jamieson M. Bourque MD, MHS.

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Appendices

Appendix 1: SPECT MPI Protocol

SPECT MPI performed as part of the study will be performed as per the most recent American Society of Nuclear Cardiology or European Association of Nuclear Medicine Imaging guidelines for SPECT MPI.

The rest and stress SPECT MPI visit may be combined with the screening or baseline visit. Results of rest and stress SPECT MPI studies that will have been performed before the subject signed the ICF (i.e., an “off-study” SPECT MPI) will be used if the SPECT MPI is performed in accordance with the study imaging manual and is performed on a camera that had already been validated for use in the study. Depending on the institution’s standard practices, the rest and stress SPECT MPI procedures will take place on the same day or on two consecutive days.

The rest and stress SPECT MPI visit may take place before or after the rest and stress F-18 Flurpiridaz PET MPI visit. Subjects who are scheduled to undergo a pharmacologic stress test will be advised not to drink or eat caffeinated substances or take any dipyridamole-containing medication or methylxanthine-containing medication in the 12 hours prior to vasodilator administration for SPECT MPI. In addition, patients who are scheduled to undergo exercise stress will also be advised to refrain from consuming any caffeinated substances, dipyridamole-containing medication, or methylxanthine-containing medication in the 12 hours prior to the exercise stress test, to allow for the use of a pharmacologic stress agent in the event that the subject does not reach the protocol required minimum 85% of age-predicted maximum heart rate or does not develop ischemic symptoms during the exercise stress.

No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise stress. For subjects on beta-blocker therapy, a determination will be made, in concert with their treating physician, if there are any conditions in which discontinuation of beta-blocker therapy are contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled hypertension). If medically safe, beta-blocker therapy will be withheld for 24 hours prior to the SPECT MPI. SPECT images will be acquired 30-60 minutes after rest injection and 15-60 minutes after stress injection. Stress testing will occur at least 30 minutes after rest image acquisition.

Appendix 2: F-18 Flurpiridaz PET MPI Protocol

The rest and stress F-18 Flurpiridaz PET MPI visit will take place before or after the SPECT MPI visit. Subjects who are scheduled for pharmacologic stress will be advised not to drink or eat caffeinated substances or take dipyridamole-containing medication or methylxanthine-containing medication in the 12 hours prior to vasodilator administration for F-18 Flurpiridaz PET MPI. In addition, patients who are scheduled to undergo an exercise stress test will be advised to refrain from consuming any caffeinated substances, dipyridamole-containing medication, or methylxanthine-containing medication within 12 hours prior to the exercise stress test to allow for the use of a pharmacologic stressor in the event that the patient does not reach the protocol required a minimum 85% of APMHR or does not develop ischemic symptoms.

No food will be allowed within 3 hours prior to either the pharmacologic stress or exercise stress. For subjects on beta-blocker therapy, a determination will be made, in concert with their treating physician, if there are any conditions in which discontinuation of beta-blocker therapy are contraindicated (e.g., tachyarrhythmias, uncontrolled or poorly controlled hypertension). If medically safe, beta-blocker therapy will be withheld for 24 hours prior to the F-18 Flurpiridaz PET MPI. A focused clinical screen for new or worsening symptoms indicative of unstable coronary artery disease will be conducted prior to performing any procedures at the F-18 Flurpiridaz PET MPI visit. If the clinical status screening is positive, the F-18 Flurpiridaz PET MPI visit will either be rescheduled (up to 1 time) after symptoms stabilize or the subject will be discontinued from the study.

During the rest and stress F-18 Flurpiridaz PET MPI visit, the following will be performed:

  • Blood samples for laboratory testing will be collected prior to the PET MPI and 1 hour after the last PET MPI injection. If for scheduling reasons, the study SPECT or study PET MPI must occur rapidly after the screening visit (e.g., within 48 hours), an additional blood sample may be analyzed by local labs specifically to determine if the subject meets exclusion criteria (i.e., serum creatinine, AST, ALT and total bilirubin). For all subjects, blood will be sent for central analysis of all protocol-specified laboratory parameters, whether or not blood is sent to a local lab for limited biochemical analysis for screening purposes (as noted above).

  • Urine samples for laboratory testing will be collected prior to the PET MPI.

  • Pregnancy test, for women of child-bearing potential will be performed.

  • Concurrent medications will be recorded.

  • Vital signs will be recorded. For rest PET MPI, vital signs will be collected up to 20 min prior to dose and 30 (± 5) minutes post-dose. For stress PET MPI, vital signs will be collected up to 20 minutes prior to dose (if > 60 minutes between rest and stress injections) and 30 (± 5) minutes post-dose.

  • Pulse oximetry will be recorded.

  • Eight 12-lead ECG recordings will be performed.

  • A physical examination will be performed.

  • If neurologic abnormalities are found during the physical examination, a full neurologic examination will be performed.

  • During the rest test, all subjects will receive an IV bolus injection of F-18 Flurpiridaz injection in a large peripheral vein. The dose (volume and radioactivity) will be recorded.

  • A stress test (exercise or pharmacologic) will be performed after the rest test, and on the same day. The type of stress (exercise or pharmacologic) will be the same type used for that subject for the SPECT MPI test.

  • For subjects who received a pharmacologic stressor during the stress SPECT MPI, the same agent and dose will be used during the stress F-18 Flurpiridaz PET MPI test. During pharmacologic stress, radiopharmaceutical injection will be administered during the peak vasodilatory effect.

  • If adenosine is used as a pharmacologic stressor, the F-18 Flurpiridaz injection and the adenosine must be administered through separate lines or through separate ports of the same IV line. Note: Central lines should NOT be used for the administration of F-18 Flurpiridaz injection. The F-18 Flurpiridaz injection will be administered after the administration of the pharmacologic stressor. The administration of F-18 Flurpiridaz injection will be timed to coincide with maximal coronary vasodilation, which depends on the vasodilatory agent used.

  • For a subject who underwent exercise stress for SPECT MPI, the investigator is required to use the same exercise stress protocol for the F-18 Flurpiridaz injection PET that was used for the SPECT MPI, unless otherwise clinically indicated.

  • During exercise stress, the radiopharmaceutical for both SPECT and PET should be administered at peak stress, defined as ≥ 85% of the APMHR or following the occurrence of typical cardiac ischemic symptoms. Patients should continue to exercise for an additional 1-2 minutes, as clinically advisable, after the radiopharmaceutical injection. If a patient cannot reach the study-required minimum of 85% of the APMHR or does not develop ischemic symptoms, the radiopharmaceutical should not be administered.

  • The standard clinical practice should be used for determining early termination of exercise or pharmacologic stress testing in the presence of any absolute or relative indications, including the presence of ischemic symptoms (i.e., angina, or angina equivalent) for early termination. The exercise stress test should be performed only by experienced site personnel with access to resuscitation equipment.

  • Injection of rest and stress doses of F-18 Flurpiridaz will occur at least 30 minutes apart.

  • Resting and pharmacologic stress PET images will be acquired as a single, 15-minute dynamic list-mode acquisition with cardiac gating. Imaging will start at the time of F-18 Flurpiridaz injection.

  • Exercise stress PET images will be acquired as a single 10-minute list-mode static acquisition with cardiac gating that will start 15-25 minutes post-injection.

  • At 1 hour after administration of F-18 Flurpiridaz injection for the stress exam, a physical examination will be performed.

  • If any neurologic abnormalities are noted during the physical examination, a full neurologic examination will be performed.

  • Injection-site monitoring (immediately prior to the first injection, immediately after the first injection of IMP for the rest exam, then immediately after the second injection of IMP for the stress exam, and ultimately at 1 hour after the last injection of IMP.

  • The images acquired during the rest and stress F-18 Flurpiridaz PET MPI will be stored for the secondary blinded review.

  • All adverse events will be recorded.

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Bourque, J.M., Hanson, C.A., Agostini, D. et al. Assessing myocardial perfusion in suspected coronary artery disease: rationale and design of the second phase 3, open-label multi-center study of flurpiridaz (F-18) injection for positron emission tomography (PET) imaging. J. Nucl. Cardiol. (2021). https://doi.org/10.1007/s12350-021-02527-8

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Keywords

  • Cardiac PET
  • Myocardial perfusion imaging
  • F-18 flurpiridaz
  • Radiotracers
  • Coronary artery disease
  • Cardiovascular imaging