Study of Hepatocyte Growth Factor (HGF) Via Plasmid Vector to Improve Perfusion in Critical Limb Ischemia Patients With Peripheral Ischemic Ulcers

A Phase II Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety and Efficacy of AMG0001 to Improve Perfusion in Critical Limb Ischemia in Subjects Who Have Peripheral Ischemic Ulcers

The objective of this study is to test the hypothesis that AMG0001 treatment is safe and induces angiogenesis as detected by improved wound healing, reduction in amputation, improved pain at rest and hemodynamic measurement and to assess the effectiveness of the administrative method.

The primary goals of this study evaluating AMG0001 administration in CLI subjects will be to investigate the efficacy and safety of AMG0001. Specifically, the objectives are:

1. Assess efficacy of a dosing regimen of 4.0mg/3 mL AMG0001, administered on Days 0, 14, and 28 as measured by reduction in total wound area at Month 3.
2. Assess potential effects of angiogenesis associated with a dosing regimen of 4.0mg/3 mL AMG0001, administered on Days 0, 14, and 28 as measured by reduction in total wound area at Months 6 and 12, along with reduction in major amputations and improved pain at rest as measured on the VAS and hemodynamic measures (ABI/TBI) at Month 3 and Month 6.
3. Assess overall safety of AMG0001 in the Critical Limb Ischemia subject population as determined by physical examination, blood and urine analyses, electrocardiogram, vital signs, and by evaluation of adverse experiences during and after the course of treatment.

Inclusion Criteria:

1. Subjects will have an appropriately sized peripheral ischemic ulcer(s).

2. Subjects will have one or both of the following hemodynamic indicators of severe peripheral arterial occlusive disease:

   1. Ankle systolic pressure (in either the dorsalis pedis or posterior tibial arteries) of < 70 mmHg
   2. Toe systolic pressure < 50 mmHg

3. The subject is a poor candidate for standard revascularization treatment options for peripheral arterial disease, based on inadequate bypass conduit, unfavorable anatomy, or poor operative risk.

4. Subjects 40 years or older of either sex who have signed an informed consent form either directly or through a legally authorized representative.

5. Subjects will be on a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, etc.) as part of their standard of care, unless contraindicated. Subjects for which these agents are contraindicated will have this restriction recorded in their case report form (CRF). Subjects must be stable on these medical regimens for at least 4 weeks prior to the start of treatment.

6. If female, the subjects must be:

   1. at least one year post-menopausal, or
   2. surgically sterile, or
   3. if the subject is of child-bearing potential, she must have been practicing adequate contraception for at least 12 weeks prior to entering the study and have a negative urine pregnancy test result prior to study enrollment and agree to periodic pregnancy screening tests during the study.
   4. If female, the subject must not be breastfeeding for 30 days following administration of HGF.

7. If subject is of reproductive potential, he or she must be using an accepted and effective (barrier) form of birth control during the study.

Exclusion Criteria

1. Subjects who, in the opinion of the investigator, have a vascular disease prognosis that indicates they would require a major amputation (at or above the ankle) within 4 weeks of start of treatment.
2. Subjects with a diagnosis of Buerger's disease (thromboangiitis obliterans).
3. Subjects with hemodynamically significant aorto-iliac occlusive disease.
4. Subjects who have had a revascularization procedure within 12 weeks prior to treatment initiation that remains patent. Revascularization procedures that are evidenced to have failed (completely occluded) for >2 weeks prior to treatment initiation are acceptable.
5. Subjects who require a change in their hypertension medication (other than dosage change) as part of their standard of care within 4 weeks prior to treatment initiation.
6. Subjects with deep ulcerations with bone or tendon exposure, or clinical evidence of invasive infection (e.g., cellulitis, osteomyelitis, etc.) uncontrollable by antibiotics.
7. Subjects currently receiving immuno-suppressive medication, chemo or radiation therapy.
8. Evidence or history of malignant neoplasm (clinical, laboratory or imaging), except for fully resolved basal cell carcinoma of the skin. Patient's who had successful tumor resection or radio-chemotherapy of breast cancer more than 10 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. Patient's who had successful tumor resection or radio-chemotherapy of all other tumor types more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study.
9. Subjects who have proliferative diabetic retinopathy, severe non-proliferative retinopathy, recent (within 6 months) retinal vein occlusion, macular degeneration with choroidal neovascularization, macular edema on fundus evaluation by ophthalmologist, or intraocular surgery within 3 months.
10. Subjects with end stage renal disease (ESRD) defined as significant renal dysfunction evidenced by a creatinine of > 2.5 mg/dL, or receiving chronic hemodialysis therapy.
11. Any co-morbid condition likely to interfere with assessment of safety or efficacy endpoints, acute cardiovascular events (i.e. cerebrovascular accident [CVA], myocardial infarction [MI], etc.) within 12 weeks of treatment, or non-cardiovascular diseases that in the opinion of the investigator may result in < 3 month subject mortality.
12. A subject who has a history of hepatic cirrhosis, viral hepatitis, or HIV.
13. Subjects with a clinically significant liver enzyme abnormality (i.e., AST or ALT more than two times the upper limit of normal and/or bilirubin more than 50% above the upper limit of normal).
14. Subjects taking cilostazol (Pletal®) are eligible for inclusion, but the subject must have been taking the medication for at least 4 weeks prior to test material administration.
15. Subject who received another investigational drug for peripheral arterial disease within 90 days of randomization, have previously received any gene transfer therapy or growth factor product not approved by the United States Food and Drug Administration (FDA) or received any investigational Drug Product in another clinical trial in the 30 days prior to administration of HGF.
16. Unreliable or uncooperative subject or other severe concomitant disease(s), which the clinical investigator feels constitute(s) criteria for exclusion of a particular subject.