Primary Objective:* Assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F) Injection PET myocardial perfusion imaging (MPI) in the detection of significant CAD, as defined by invasive coronary angiography (ICA), in…
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Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The sensitivity and specificity of Flurpiridaz (18F) Injection PET MPI in the
detection of significant CAD as defined by cardiac catheterisation (ICA).
Secondary outcome
The diagnostic efficacy (sensitivity and specificity) of Flurpiridaz (18F)
Injection PET MPI compared to that of SPECT MPI, when the diagnosis of CAD by
ICA is the standard of truth, in the following:
* All subjects (key secondary endpoint)
* Female subjects
* Subjects with BMI *30 kg/m2
* Diabetic subjects
Exploratory Efficacy Endpoints:
* Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz
(18F) Injection PET MPI compared with that of SPECT MPI in the detection of
CAD, as defined by ICA, in subjects categorised by relative LV size.
* Image quality of rest and stress Flurpiridaz (18F) Injection PET MPI as
compared to that of SPECT MPI.
* Diagnostic certainty of rest and stress Flurpiridaz (18F) Injection PET MPI
as compared to that of SPECT MPI.
* Diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI as compared to
that of SPECT MPI in the detection of significant CAD in subjects undergoing
pharmacologic stress.
* Diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI as compared to
that of SPECT MPI in the detection of significant CAD in subjects undergoing
exercise stress.
* Diagnostic accuracy of Flurpiridaz (18F) Injection PET MPI as compared to
that of SPECT MPI.
* Diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI as compared to
that of SPECT MPI in the detection of multivessel CAD.
* Diagnostic performance characteristics of Flurpiridaz (18F) Injection PET MPI
as compared to those of SPECT MPI for identifying the location of significant
CAD.
* Detection of reversible defect size (extent and severity) with rest and
stress PET MPI as compared to that with SPECT MPI, and the determination of the
myocardial blood flow and the myocardial and coronary flow reserve, through use
of specific quantitation software.
Background summary
Coronary artery disease (CAD) is a major cause of death in modern
industrialised countries. CAD is the single largest cause of death in the
United States. According to data from the US National Health and Nutrition
Examination Survey (NHANES) from 2011 to 2014, the prevalence of CAD in all
adults >20 years of age was 6.3% (16.5 million Americans); and in 2014,
mortality from CAD accounted for 1 in every 7 deaths (364,593 directly related
to coronary heart disease [CHD], and there were 530,989 deaths where CHD was
mentioned). In 2017, an estimated 695,000 Americans will have a new CHD event
(defined as hospitalisation for myocardial infarction [MI] or CHD death) and
325,000 will have a recurrent event. Not only is CHD morbid, it strains
healthcare resources. In 2011, hospital care associated with MI cost the US
healthcare system $11.5 billion and CHD cost $10.4 billion, representing 2 of
the 10 most expensive hospital principal discharge diagnoses. These costs are
projected to double between 2013 and 2030. Therefore, prevention, early
diagnosis, and treatment of CAD are essential to reduce mortality.
Invasive coronary angiography (ICA) is the definitive procedure for diagnosis
of obstructive CAD. It is an invasive examination that involves
catheterisation of the heart, allowing an anatomical evaluation that defines
the presence, location, and severity of stenoses in the coronary arteries.
However, limitations exist to the sensitivity and specificity of ICA for
defining myocardial perfusion. ICA does not determine whether a stenosis
causes ischemia. ICA is restricted to the assessment of large vessels,
providing no visualisation of arterioles and capillaries. Fractional flow
reserve (FFR) assessment, a measure of the decrease in perfusion pressure
across a stenotic vessel under hyperaemic conditions, better defines the
haemodynamic consequence of a stenosis. However, FFR analysis does not account
for the presence of scar, collateral flow, or microvascular dysfunction of the
area subtended by the vessel; these limitations may affect clinical
interpretation of FFR analysis [Hussain et al 2016]. Despite guideline
recommendations for its use to define the haemodynamic significance of
intermediate stenoses, FFR is performed in only 27% of the cases where it is
indicated. Cardiac catheterisation, including FFR analysis, is not without
risk. Estimates of the incidence of periprocedural stroke range from 0.18% to
0.44%, while the incidence of coronary artery perforation ranges from 0.5% to
3%. The overall risk of periangiographic death in patients undergoing
catheterisation without intervention is about 0.08%.
Study objective
Primary Objective:
* Assess the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz
(18F) Injection PET myocardial perfusion imaging (MPI) in the detection of
significant CAD, as defined by invasive coronary angiography (ICA), in patients
with suspected CAD.
Secondary Objectives:
* Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz
(18F) Injection PET MPI compared with that of single photon emission computed
tomography (SPECT) MPI in the detection of CAD, as defined by ICA, in the
following groups of subjects:
o All subjects (key secondary endpoint)
o Female subjects
o Subjects with body mass index (BMI) *30 kg/m2
o Diabetic subjects
* Assess the safety of Flurpiridaz (18F) Injection PET MPI.
Exploratory Objectives:
* Evaluate the diagnostic efficacy (sensitivity and specificity) of Flurpiridaz
(18F) Injection PET MPI compared with that of SPECT MPI in the detection of
CAD, as defined by ICA, in subjects categorised by relative left ventricle (LV)
size.
* Assess the image quality of rest and stress Flurpiridaz (18F) Injection PET
MPI as compared to that of SPECT MPI.
* Assess the diagnostic certainty of rest and stress Flurpiridaz (18F)
Injection PET MPI compared to that of SPECT MPI.
* Assess the diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI
compared to that of SPECT MPI in the detection of significant CAD in patients
undergoing pharmacologic stress.
* Assess the diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI
compared to that of SPECT MPI in the detection of significant CAD in patients
undergoing exercise stress.
* Assess the diagnostic accuracy of Flurpiridaz (18F) Injection in PET MPI
compared to that of SPECT MPI.
* Assess the diagnostic efficacy of Flurpiridaz (18F) Injection PET MPI as
compared to that of SPECT MPI in the identification of subjects with
multivessel CAD.
* Assess the diagnostic performance characteristics of Flurpiridaz (18F)
Injection PET MPI compared to that of SPECT MPI for identifying the location of
significant CAD.
* Assess the size (extent and severity) of reversible defects with rest and
stress PET MPI compared to SPECT MPI.
* Evaluate the myocardial blood flow by using specific quantitation software.
* Evaluate the myocardial and coronary flow reserve by using specific
quantitation software.
Study design
This is a Phase 3, prospective, open-label, international, multicentre study of
Flurpiridaz (18F) Injection for PET MPI in patients referred for ICA because of
suspected CAD. Five hundred and fifty-two (552) evaluable subjects will be
enrolled in this study, and will undergo SPECT MPI and Flurpiridaz (18F)
Injection PET MPI, prior to ICA.
Patients can be considered for enrolment if:
* They are being scheduled via written documentation at the time of enrolment
to undergo ICA, and
* They have undergone a clinically indicated SPECT study which meets all
study-specified imaging and stress testing criteria, or are willing to undergo
SPECT MPI for the purposes of the clinical study.
Intervention
Flurpiridaz (18F) Injection is a novel PET MPI agent labelled with the
radioisotope fluorine-18 and administered as an intravenous (IV) injection.
All subjects will receive 2 IV boluses of Flurpiridaz (18F) Injection in a
large peripheral vein: 1 at rest and 1 during stress. The dosages of
Flurpiridaz (18F) Injection administered at rest and during stress conditions
will not exceed a total of 14 mCi (520 MBq) for an individual subject.
SPECT agents utilised for the purposes of this clinical study will be
administered as per American Society of Nuclear Cardiology or European
Association of Cardiovascular Imaging standards corresponding to study site
location. For each subject, the same stress type (pharmacologic or exercise)
that was used in the SPECT MPI should be used for the Flurpiridaz (18F)
Injection PET MPI. Also, if pharmacological stress is used, the same agent and
the same dose of pharmacological stress agent should be used for both types of
imaging for the same subject.
Pharmacological stress agents utilised for the purposes of this clinical study
will be administered according to the respective Package Insert (as applicable)
or American Society of Nuclear Cardiology or European Association of
Cardiovascular Imaging standards corresponding to study site location. During
pharmacologic stress, radiopharmaceutical injection will be administered during
the peak vasodilatory effect according to the respective Package Insert (as
applicable) of each stressor.
Study burden and risks
The study medicine and/or the procedure under investigation may cause side
effects. A total of 1012 participants have received flurpiridaz (F-18)
injections in earlier clinical studies. In the first three research studies,
there were no reported side effects of flurpiridaz (F-18). In the most recent
study of flurpiridaz (F-18), about 6 percent of the study participants reported
side effects that study doctors judged may be related to flurpiridaz (F-18).
These uncommon side effects included:
* Headache
* Feelings of pressure in the chest
* having a metallic taste in mouth
* diarrhoea
* shortness of breath
* flushing
* nausea
* numbness
* rapid or irregular heartbeat
* cough
* severe itching of skin
None of these events were serious and all resolved in a short period of time
without any complications or remaining effects. While there have been no
significant side effects related to flurpiridaz (F-18) to date, it is possible
that there are side effects that are not yet known.
Stress Agent Risks
If ythe subject does not undergo an exercise stress test, then in addition to
the study drug, ythe subjerct will receive one of these medicines to imitate
the effects of exercise: adenosine, dipyridamole and regadenoson. There are
also medicines sometimes given to reverse the effects of stress agents (e.g.
Aminophylline, theophylline). The side effects associated with these products
are listed in each of their package inserts.
Exercise (treadmill or bicycle) Stress Testing Risks
The risk of this stress testing procedure includes: disorders of heart rhythm,
abnormal blood pressure responses, and in very rare instances; heart attack and
even death. Precautions will be taken by carefully monitoring the heart by ECG,
blood pressure and how the subject is feeling before, during, and after the
stress test.
IV and Blood Sampling Risks
The maximum amount of blood samples taken from the subject will not be more
than 50 mL during this study. While collecting blood for the laboratory exams
or when placing the IV catheter, the subject will feel a quick needle prick
which may cause bleeding, bruising and possible infection at the injection
site.
Beta-Blocker Withdrawal Risks
If the subject is on beta-blocker therapy, and it is deemed medically safe by
the treating physician, the subject may be asked to stop the beta-blocker
therapy 24 hours prior to the SPECT and PET stress test. Holding beta-blocker
therapy prior to a stress test is consistent with current clinical guidance on
stress testing. The following symptoms have been reported in some instances of
beta-blocker withdrawal:
* Patients suffering from cardiovascular diseases may notice their condition
worsening, which could increase risk of heart attack.
* The symptoms of angina (chest pain) may become more intense
Cardiac Catheterization Risks
To be enrolled in this study subjects will have been scheduled for a cardiac
catheterization. The cardiac catheterization is not a research procedure, but
we will be comparing the data from the cardiac catheterization with the PET and
SPECT imaging studies.
Nightingales Lane -
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Nightingales Lane -
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Listed location countries
Age
Inclusion criteria
1) The subject is a man or woman,18 years of age.
2) The subject has read, signed, and dated an informed consent form (ICF) prior
to any study procedures being performed, and is willing to allow the study
investigator to make the subject*s medical records available to GE Healthcare
(including clinically indicated SPECT studies occurring prior to the signing of
the ICF as stipulated in inclusion criteria #4).
3) At the time of enrolment, the subject has been scheduled via written
documentation to undergo an ICA for the assessment of CAD.
4) The subject has undergone a clinically indicated SPECT which meets all
study-specific imaging and stress testing criteria and conforms to local
guidelines (such as American Society of Nuclear Cardiology or European
Association of Nuclear Medicine), OR the patient is willing to undergo SPECT
MPI for the purposes of the clinical study.
5) The subject is male or is a nonpregnant, nonlactating female who is either
surgically sterile or is post-menopausal. For women of childbearing potential,
the results of either a urine or serum human chorionic gonadotropin pregnancy
test must be negative; these subjects must be practicing appropriate birth
control from the time of the screening to 30 days after the radiopharmaceutical
administration.
Exclusion criteria
1) Patients who are pregnant, may possibly be pregnant, or wish (including
their partners) to become pregnant during the study period, or are lactating.
2) Patients who are unable to undergo all of the imaging procedures.
3) Patients who have an established diagnosis of CAD as confirmed by any of the
following:
a. Previous myocardial infarction (MI);
b. Previous cardiac catheter angiography showing *50% stenosis;
c. Previous coronary revascularisation, such as percutaneous coronary
intervention (PCI), thrombolysis or coronary artery bypass graft (CABG)
placement.
4) Patients incapable of undergoing either exercise or pharmacological cardiac
stress testing
5) Patients who have a current illness or pathology that, in the opinion of the
investigator, would pose a significant safety risk for the patient during
cardiac stress testing.
6) For patients for whom pharmacological stress testing is being considered,
the following additional exclusion criteria will apply:
a. Known hypersensitivity to adenosine, regadenoson, dipyridamole, or
aminophylline;
b. Use of a caffeinated substance, dipyridamole-containing medication, or
methylxanthine-containing medication within 12 hours prior to vasodilator
administration;
c. Bronchoconstrictive or bronchospastic disease that in the opinion of the
investigator poses a significant safety risk for the patient;
d. Second- or third-degree atrioventricular block or sinus node dysfunction
without functioning artificial pacemaker;
e. Any additional contraindication to the pharmacological stress agent listed
in the product*s package insert/summary of product characteristics (SmPCs).
7) Patients with unstable cardiovascular condition, including but not limited
to:
a. Unstable angina, acute coronary syndrome within 6 months of enrolment;
b. Transient ischaemic attack/stroke within 3 months of enrolment;
c. Significant congenital heart disease;
d. Uncontrolled hypertension;
e. Uncontrolled tachyarrhythmia leading to symptoms or haemodynamic compromise.
8) Documented history of heart failure and/or cardiomyopathy (including
nonischaemic cardiomyopathy, hypertrophic obstructive cardiomyopathy, or
infiltrative cardiomyopathy) and/or prior LV ejection fraction (LVEF) <50%.
9) Primary haemodynamically significant uncorrected valvular heart disease,
obstructive or regurgitant.
10) Patients scheduled for or planning to undergo any cardiac interventional
procedures between enrolment and ICA.
11) Patients with screening laboratory findings as follows:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater
than 3 times the upper limit of normal;
b. Total bilirubin *2.0 mg/dL (34.2 µmol/L);
c. Serum creatinine *3.0 mg/dL (265.2 µmol/L).
12) Patients who present with any clinically active, serious, life-threatening
disease, medical, or psychiatric condition, and/or who have a life expectancy
of <6 months, or for whom study participation may compromise their management;
and patients whom the investigator judges to be unsuitable for participation in
the study for any reason.
13) Patients undergoing evaluation for heart transplantation or with history of
heart transplantation.
14) Patients enrolled in another clinical study within the 30 days prior to
being enrolled in this study or scheduled to participate in another clinical
study during the 7-day follow-up period of this study.
15) Patients previously enrolled in this study or any Flurpiridaz (18F)
Injection study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-005011-14-NL |
| ClinicalTrials.gov | NCT03354273 |
| CCMO | NL66183.100.18 |