Safety and Efficacy Study of Ad2/Hypoxia Inducible Factor (HIF)-1α/VP16 Gene Transfer in Patients With Intermittent Claudication

Exclusion Criteria

• •Patients with either current or any history of Critical Limb Ischemia (CLI; that is, patients classified as Rutherford Category 4 \[ischemic rest pain\], Rutherford Category 5 \[non-healing ischemic ulcers and minor tissue loss\], or Rutherford Category 6 \[non-healing ischemic ulcers and major tissue loss\]).
• •Patients in whom arterial insufficiency in the lower extremity is the result of acute limb ischemia or an immunological or inflammatory non-atherosclerotic disorder (eg, thromboangiitis obliterans \[Buerger's Disease\]) and systemic sclerosis \[both limited and diffuse forms\]).
• •A PAD-specific surgical revascularization procedure within 6 months of enrollment or a PAD-specific percutaneous procedure within 3 months of enrollment, or patients likely to require a PAD-specific revascularization procedure within 6 months after Enrollment.
• •Patients with aortoiliac disease that limits inflow in either leg: a. Patients with concomitant aortoiliac disease (i.e., patients with a significant component of inflow disease in the distal aorta, common or external iliac, or proximal common femoral artery) as assessed by an imaging modality (e.g., segmental limb pressures and waveform analysis, duplex ultrasound scanning, magnetic resonance angiography, or radio-contrast arteriogram) performed within 1 year prior to Enrollment. If subject has had a bypass after the imaging study, then documentation of graft patency is required within 6 months prior to Enrollment; b. If it is suspected at Screening that a patient has aortoiliac disease based on vascular examination, an imaging modality (e.g., segmental limb pressures and waveform analysis, duplex ultrasound scanning, magnetic resonance angiography, or radio-contrast arteriogram) must be performed to rule it out if there is not one available within the times specified above. If there is no suspicion of aortoiliac disease in the Principal Investigator's judgment, an imaging test at Screening is not required for study purposes.
• •Patients in whom walking impairment due to pain in the index leg is the result of these nonatherosclerotic comorbid conditions: venous claudication, chronic compartment syndrome, peripheral nerve pain (e.g., severe peripheral neuropathy), pseudoclaudication caused by spinal cord compression, or acute limb ischemia which, in the Principal Investigator's judgment are severe enough to confound the assessment of the patient's IC.
• •Conditions other than IC of significant severity that could confound PWT on the standardized exercise treadmill test causing premature or inconsistent termination of exercise (e.g., angina pectoris, heart failure \[New York Heart Association {NYHA} Classes III and IV\], respiratory disease \[e.g., chronic obstructive pulmonary disease\], orthopedic disease, neurological disorders, rheumatologic disorders \[e.g., severe degenerative joint diseases\], dyspnea, fatigue, prior lower limb amputation, including amputations proximal to the metatarsal or phalangeal joints).
• •Presence or history of cancer within 5 years of enrollment or not current with recommended screening guidelines for colorectal, lung, prostate, breast, cervical, and uterine cancers, with the exception of low grade and fully resolved non-melanoma skin malignancy.
• •Patients with a well-defined clinical or genetic disorder predisposing to malignancy should be excluded (e.g., von Hippel Lindau, familial polyposis coli, BRCA1, BRCA2, etc).
• •Patients with baseline funduscopic evidence of active proliferative diabetic retinopathy, preproliferative diabetic retinopathy, or wet AMD AND/OR Patients with a history of treatment for active proliferative diabetic retinopathy or wet AMD within 5 years of enrollment.
• •Diabetes type 1 (juvenile onset)
• •Poorly controlled type 2 diabetes (ie, HbA1C \>10%) at Screening
• •Active hepatitis defined as clinically significant increase in liver enzymes (ie, 3 times the ULN) or other current infectious disease
• •Patients with symptoms of respiratory infection at time of Screening and/or randomization period and/or patients who have been on systemic or oral antibiotics for active infection within 2 weeks of study drug administration.
• •Patients with clinically significant abnormal hematology (eg, hematocrit \< 30%, white blood cell count \> 14,000), blood chemistry, renal, hepatic, or other laboratory parameters that could be the result of an underlying malignancy or systemic infection (e.g., serum creatinine ≥ 2.5 mg/dL), as judged by the investigator.
• •Patients with the following comorbidities who may not be healthy enough to successfully complete all protocol requirements or in whom results may be particularly difficult to assess: Concurrent severe congestive heart failure (NYHA Classes III and IV); Life-threatening ventricular arrhythmias, unstable angina (characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged duration), and/or myocardial infarction within 4 weeks before enrollment; Coronary artery bypass grafting or percutaneous coronary intervention within 3 months before enrollment; A renal and/or carotid revascularization procedure within 1 month of enrollment; Transient ischemic attack within 3 months before enrollment; Deep vein thrombosis within 3 months before enrollment; Severe chronic obstructive pulmonary disease (room air arterial PO2 \< 60 mmHg or PCO2 \> 50 mmHg, or abnormal pulmonary function tests (FEV1 \< 1.2 L/sec); Thrombocytopenia (defined as platelet count \< 100,000/mm3); Undergoing hemodialysis; Patients with immunocompromised conditions, organ transplant recipients and/or need for immunosuppressive therapy; Neurological dementia (i.e., Alzheimer's Disease); Hemorrhagic stroke
• •Patients with a known allergy to the vehicle, placebo control, or any other medications or imaging agents required for participation in this study.
• •Fertile women who are pregnant (as confirmed by a serum pregnancy test at the Screening Visit and a urine pregnancy test at Day 0 prior to study drug administration), nursing, or using either no or an inadequate form of contraception.
• •Fertile men and women who are not willing to use barrier-type contraception for at least 90 days post-treatment.
• •Patients with a recent history of alcoholism or drug abuse, or severe emotional, behavioral or psychiatric problems, who may not be able to adequately comply with the requirements of the study.
• •Patients receiving experimental medications or participating in another study using an experimental drug or experimental procedure within 30 days of enrollment into this study.
• •Patients previously enrolled in a prior angiogenic gene therapy clinical study, unless patient was a known placebo patient.