Ad5FGF-4 In Patients With Refractory Angina Due to Myocardial Ischemia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a single intracoronary infusion of an adenovirus serotype 5 virus expressing the gene for human fibroblast growth factor-4 (Ad5FGF-4) is effective in improving angina-limited exercise duration, angina functional class, frequency of angina attacks, frequency of nitroglycerin usage, and quality of life. Half of the study participants will receive Ad5FGF-4, and half will receive placebo. The primary endpoint is the change from baseline to Month 6 in Exercise Tolerance Test (ETT) duration. Long-term safety of Ad5FGF-4 will also be assessed.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter, Phase 3 Study to Evaluate the Safety and Efficacy of Ad5FGF-4 in Patients With Refractory Angina Due to Myocardial Ischemia

Conditions
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Angina, Stable

Intervention / Treatment
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* Biological: Ad5FGF-4
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 55-75 years of age inclusive Refractory angina CCS Class III or IV At least 3 angina episodes per week Diagnostic coronary angiogram in the past 12 months confirming the presence of coronary artery disease in patients who are not candidates for standard interventions (PCI or CABG) Patients without significant and adequate reduction or relief of angina in spite of treatment with at least two functional classes of chronic anti-angina medication at the maximally tolerated dose. Functional classes of anti-angina medications include β-blockers, calcium channel blockers, nitrates, and metabolic modulators (i.e. ranolazine). Participants must have been on a stable anti-angina medication regimen for at least 4 weeks before signing the informed consent form. Documented clinical evidence of inducible ischemia on stress testing within the past 6 months [e.g. nuclear perfusion imaging (stress SPECT or PET), stress ECHO, stress MRI, stress ETT (≥1 mm ST Segment depression)]. Maximal exercise duration of 3-8 minutes on ETT (Modified Bruce Protocol), with patient physically unable to continue due to angina or angina equivalent (e.g. exhaustion/dyspnea), or when ETT is stopped by person administering the ETT. Patient develops ≥1mm ST segment depression on each of the qualifying baseline ETT Left ventricular ejection fraction (LVEF) of ≥ 30% Postmenopausal female patients, women of childbearing potential and men willing to use an effective contraception method while in the study and/or who agree not to become pregnant or make their partner pregnant throughout the study and during one year after administration of the study drug Female subjects of childbearing potential who have a negative urine pregnancy test and are willing to use an acceptable form of birth control during the study. For the purpose of this study, a female of childbearing potential is a female who is not postmenopausal for greater than 2 years, has not had a tubal ligation, and has not had a hysterectomy. For the purpose of this study, the following are considered acceptable methods of birth control: Oral contraceptives, contraceptive patches/implants Intrauterine device (IUD) together with condom or spermicide for at least three months Condom and spermicide Abstinence with a documented second acceptable method of birth control should the subject become sexually active Willing and able to comply with all study requirements, including adherence to the assigned strategy, medical therapy, and follow-up Provided written informed consent Exclusion Criteria Female patients who are pregnant, lactating (breast milk feeding), or planning a pregnancy during the course of the study and one year after administration of the study drug. Women of childbearing potential who are not using an acceptable method of birth control (i.e., IUD, oral contraceptive plus barrier contraceptive, hormone delivery system plus barrier contraceptive or condom in combination with contraceptive cream, jelly or foam). Women of childbearing potential with a positive urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before randomization. Patients with unstable angina for whom an immediate revascularization procedure (PCI or CABG) is indicated Patients for whom a cardiac revascularization procedure (PCI or CABG) is planned in the next 3 months Myocardial infarction within the past 3 months prior to the Screening visit Congestive heart failure New York Heart Association (NYHA) Class IV Myocarditis or restrictive pericarditis Diagnostic coronary angiogram finding of left main coronary stenosis ≥70% (unless the patient has a patent graft or collateral vessels supplying the left coronary circulation) or proximal stenoses ≥70% in all major coronary conduit vessels (coronary arteries and bypass grafts) A single patent coronary conduit (for example, totally occluded RCA and LCx with no bypass grafts. Patient will not tolerate balloon occlusion of the LAD for infusion) Patients whose angiogram shows a good anatomy for angioplasty and who are candidates for that procedure. Patients without a prior angiogram or angiogram report are excluded. Clinically significant aortic or mitral valvular heart disease Life-threatening coronary ostial stenosis that precludes adequate catheter engagement in any target vessel, unless the vessel can be accessed via a patent bypass graft Coronary artery to venous communications, which bypass the coronary capillary bed Untreated life-threatening ventricular arrhythmias Uncontrolled arterial hypertension with systolic blood pressure >140 mm Hg and/or diastolic pressure >100 mm Hg CABG surgery within the past 6 months, unless those grafts are now occluded Percutaneous coronary intervention (PCI) within the past 3 months, unless the stented/dilated vessel(s) are now occluded Enhanced external counterpulsation (EECP) within 3 months prior to the start of screening evaluations Prior treatment with spinal cord stimulation Prior treatment with coronary sinus reducer Transmyocardial or percutaneous myocardial laser revascularization within the past 12 months Prior treatment with any cardiovascular gene or cell therapy within the past 12 months Active SARS-CoV-2 infection (COVID-19) Any major organ disease or any medical disease or condition that substantially impairs life expectancy History of cancer within the past 5 years, other than basal cell carcinoma, or patients with any laboratory or physical exam or diagnostic procedure finding suggestive of current malignancy Moderate to severe non-proliferative or proliferative retinopathy from any cause, clinically significant macular edema, or previous pan-retinal photocoagulation therapy Heparin induced thrombocytopenia or history of idiopathic thrombocytopenic purpura or other medical condition causing thrombocytopenia Serum glutamic pyruvic transaminase (SGPT) level greater than 2.0 times the upper limit of the laboratory normal range. Bilirubin level ≥ 2.0 mg/dL Serum creatinine ≥ 2.5 mg/dL Platelet count < 100,000/μL White blood cell count < 3,000/μL HbA1c > 9% in patients with diabetes Positive test for hepatitis B or C Positive test for human immunodeficiency virus (HIV) Prior anaphylaxis reaction to iodinated contrast agents Patients who are known to be immunosuppressed or are receiving chronic treatment with immunosuppressive drugs Received an investigational drug or biologic within 30 days of screening or are currently participating in an investigational drug, biologic or device trial History of alcohol or drug abuse History of non-compliance with medical therapy

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Ad5FGF-4<br>Ad5FGF-4, administered one time at 6x10e9 viral particles in buffer, and maximally-tolerated medical therapy for angina. | Biological: Ad5FGF-4<br>* Ad5FGF-4 administered via intracoronary infusion using standard balloon catheter, and under conditions of transient ischemia.<br>* Other names: alferminogene tadenovec;|
| Placebo Comparator: B: Placebo<br>Placebo buffer, administered one time, and maximally-tolerated medical therapy for angina. | Biological: Placebo<br>* Placebo buffer administered via intracoronary infusion using standard balloon catheter, without transient ischemia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Exercise Tolerance Test (ETT) duration | Modified Bruce Protocol with exercise duration limited by angina or angina equivalent | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in patient functional status (CCS class) | Canadian Cardiovascular Society (CCS) angina classification | Baseline and Month 6 | 
| Change in weekly angina frequency | Average weekly angina episodes | Baseline and Month 6 | 
| Change in weekly nitroglycerin usage | Average weekly nitroglycerin usage | Baseline and Month 6 | 
| Change in quality of life | Seattle Angina Questionnaire | Baseline and Month 6 | 
| Safety of Ad5FGF-4 | Adverse events and clinical laboratory testing | Through Month 6 | 
| Long-term safety of Ad5FGF-4 | Occurrence of clinically significant events | Through Month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory angina, myocardial ischemia, angiogenesis