EndocardialVascularEndothelialGrowth Factor D(VEGF-D)Gene Therapy for the Treatment of Severe Coronary Heart Disease

Study objective(s):

The purpose of the study is to evaluate the safety and efficacy of catheter mediated endocardial adenovirus VEGF-D gene transfer in patients with severe coronary heart disease to whom revascularisation cannot be performed ("no option -patients"). The primary objective is safety of the gene therapy and the secondary objective is the efficacy of gene therapy to improve myocardial perfusion as measured by MRI, PET and left ventricular function as measured by echocardiography as well as to improve functional status as measured by bicycle ergometer test. Quality of life will be monitored with a personal interview and the consumption of nitrate medication.

Study design:

This is a randomised, single-blinded, placebo controlled single centre Phase I study for patients with coronary heart disease to whom no other treatment than standard medication is available. Patients will be randomized 4:1 to the treatment group and control group. Control patients will not be treated with gene injections but only with cardiac electroanatomical mapping.

Study population:

Up to thirty patients will be recruited from the area of Kuopio University Hospital in the study. The patients will be selected for the trial on the basis of coronary angiogram imaging. Only those patients who are not eligible for the coronary angioplasty or bypass operation ("no option -patients") due to diffuse coronary stenosis, small coronary vessels, repeated revascularisation or too high risk for operation, will be included.

Assessments:

Assessments for safety are recording of adverse events (Appendix 4), laboratory assessments and transthoracic echocardiography. Assessments for efficacy are clinical symptoms and need for nitrate medication, cardiac MRI, PET and bicycle ergometer test. Other assessments are 24-hour Holter recording, transthoracal echocardiography, quality of life and PCR reactions for the detection of gene and virus vector.

Investigational drug product:

First generation replication-deficient AdVEGF-D produced in 293 cells (refer to product master file (PMF-VD-08-001)) will be injected into ten sites in the endocardium. In the beginning, an escalating dose of 1x109, 1x1010 and 1x1011 vpu of virus in a total volume of 2 ml (10 times 0.2 ml) will be used. On the basis of fifteen patients an interim analysis will be performed to evaluate the most suitable dose of virus which will be used for the rest of the study patients. Control patients will not be treated with drug product, only electroanatomical mapping will be performed.

Inclusion criteria

• informed consent signed,
• age between 30 and 80 years,
• significant angina pectoris (CCS II-III) despite of maximal medication,
• significant stenosis in coronary angiography (stenosis > 60 %),
• contraindication to coronary angioplasty or by pass operation (diffuse or distal stenosis,
• chronic total occlusion,
• vessels with difficult anatomy,
• stenosis with severe calcifications,
• stenosis in small vessels (< 2.5 mm)),
• reversible myocardial perfusion defects detected by pharmacological adenosine or dobutamine assisted perfusion MRI,
• angina pectoris or ischemic ST-depression (> 1 mm) in the exercise test,
• left ventricle wall > 8 mm detected by transthoracal echocardiography (treatment area).

Exclusion criteria

• women in fertile age,
• patients with type 1 diabetes mellitus or severe end-stage type 2 diabetes mellitus,
• diabetic retinopathy,
• atrial fibrillation,
• clinically significant anemia (hemoglobin count < 120 mg/l in male, < 110 mg/l in female; hematocrit < 0.36), leukopenia (b-leukocyte count < 3.0x109/l), leukocytosis (b-leukocyte count > 12.0x109/l) or thrombocytopenia (b-thrombocyte count < 100x109/l), renal insufficiency (s-creatinine > 160mg/l),
• liver insufficiency (s-alanine amino transferase and s-alcaline phosphatase over 2 x normal),
• haematuria of unknown origin,
• severe hypertension (systolic blood pressure > 200 mmHg or diastolic blood pressure > 110 mmHg) or significant hypotension (systolic blood pressure < 90mmHg),
• significant obesity (BMI > 35),
• cardiac pacemaker,
• acute infection,
• immunosuppressive medication,
• significant impairment of the left ventricular function (EF < 25% in TTE or CO < 2 l in MRI),
• congestive heart failure,
• haemodynamically significant (gradus 3-4/4) aortic regurgitation or other heart disease needing surgery,
• recent ( < 6 weeks) acute coronary syndrome or myocardial infarction (elevated CK-MB or cardiac troponin),
• PCI or CABG or TIA/stroke,
• previous or current malignancy.