Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia

A Phase 3 Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety and Efficacy of AMG0001 in Subjects With Critical Limb Ischemia

Study to Evaluate the Efficacy and Safety of AMG0001 in Subjects with Critical Limb Ischemia.

This is a double-blind, randomized, placebo-controlled, phase 3, multinational, multicenter study of AMG0001 (HGF plasmid) in subjects with Critical Limb Ischemia (CLI).

Inclusion Criteria:

1. Subjects with CLI (Severe Rutherford 4 and Rutherford 5) who have:

   • No option for revascularization by endovascular intervention or surgical bypass

   or

   • Poor option (high risk) for revascularization by surgery and no option for an endovascular intervention (see Section 3.1 Study Population for full definition for appropriate inclusions).

2. Subjects 40-90 years of either gender who have signed an informed consent form either directly or through a legally authorized representative.

3. Subjects currently are taking a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, etc.) for 2 weeks or more prior to Day 0 as part of their standard of care, unless contraindicated. Subjects for whom these agents are contraindicated will have the reason for contraindication recorded in their case report form (CRF).

4. If female, the subjects must not be of child bearing potential, e.g., post-menopausal or surgically sterile.

5. If a male subject is of reproductive potential, he must agree to use an accepted and effective (barrier) form of birth control starting with the first dose of study product and continue for 12 weeks from the last dose of study product. This applies to both courses of treatment.

6. Subjects with a previous medical history of myocardial infarction and/or stroke should have adequate management of risk factors to prevent secondary occurrence. (See Section 4.2 Medical History for guidelines on appropriate secondary prevention.)

7. Subjects should have the ability to understand the requirements of the protocol and agree to return for the required study visits, assessments and follow up.

   • The index leg will be the leg with the greater severity of CLI disease. Entry requirements apply to the index leg. The index leg may also be referred to as the treated leg or affected leg in the text of this protocol or other study documents. If the subject has two legs that have the same Rutherford classification (severe Rutherford 4 or Rutherford 5) and are both eligible for treatment, the leg with greater disease severity (based on more extensive necrosis or more extensive/deeper ulceration(s), difference in ABI (ankle brachial index) or TBI (toe brachial index) ≥ 0.1, and/or more extensive vascular disease based on the angiogram) will be chosen as the index leg. If there is no clinical, hemodynamic or angiographic or other evidence to determine which leg has greater disease severity, the subject will be excluded from the study.
   • These entry criteria will be enforced (prior to randomization) by the Sponsor, as well as an Entry Committee who will review all relevant clinical data including but not limited to medical illness, CLI status, the findings of an angiogram, ulcer photographs and measurements and hemodynamic data.

Exclusion Criteria:

1. Subjects whose CLI status is unstable (spontaneous marked improvement or marked worsening during the screening period) or who have excessive tissue necrosis that is unlikely to benefit from medication, or those poor option subjects requiring immediate revascularization by surgery. Stability of the CLI status will be confirmed by the Principal Investigator prior to randomization and retrospectively reviewed by the Adjudication Committee.
2. Subjects who may require a major amputation (amputation at or above the ankle) within 4 weeks of Day 0 (± 4 weeks of Day 0).
3. Subjects with ulcers with exposure of tendons, osteomyelitis or uncontrolled infection or with the largest ulcer that is greater than 20 cm2 in area (>10 cm2 area if on the heel).
4. Subjects with purely neuropathic, or with venous ulcers.
5. Subjects in Rutherford 6 class.
6. Subjects who have had revascularization by surgery or angioplasty within 3 months, unless the procedure has failed based on the anatomy or the hemodynamic measurements.
7. Subjects with a diagnosis of Buerger's disease (Thrombo-angiitis Obliterans).
8. Subjects currently receiving immunosuppressive, chemo or radiation therapy.
9. Evidence or history of malignant neoplasm (clinical, laboratory or imaging) except for successfully excised basal cell or squamous cell carcinoma, or successfully excised early melanoma of the skin. Subjects, 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. Subjects, who had successful tumor resection or radio-chemotherapy of all other tumor types and have been in remission for more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. A dermatological exam will have ruled out any skin cancer.
10. Subjects who have proliferative retinopathy, or moderate or severe non-proliferative retinopathy, from any cause (ETDRS Score > 35), clinically significant macular oedema or previous panretinal photocoagulation therapy (Results from the Early Treatment Diabetic Retinopathy Study. Ophthalmology May 1991 Supplement 98: 823-833).
11. Females of child-bearing potential defined as subjects that are not surgically sterile or post-menopausal.
12. Subjects with severe renal disease defined as significant renal dysfunction evidenced by an estimated creatinine clearance of <30 mL/minute (calculated using the Cockcroft Gault formula), or receiving chronic hemodialysis therapy.
13. Any co-morbid condition likely to interfere with assessment of safety or efficacy endpoints, acute cardiovascular events (i.e., CVA (cardiovascular accident), MI (myocardial infarction), etc.) within 3 months of treatment, or any disease that in the opinion of the Investigator may result in subject mortality in less than 3 months.
14. Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver).
15. A subject with HIV, AIDS, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc).
16. Subjects who have a significant psychiatric disorder or mental disability that could interfere with the subject's ability to provide informed consent or comply with study procedures.
17. Subjects with a current, uncorrected history of alcohol or substance abuse.
18. Diabetic subjects with an uncorrected HbA1c > 9.0% during the screening period.
19. Subjects that have been administered rhPDGF (e.g, becaplermin) or other growth factors locally within one month of randomization.
20. Subjects who have received another investigational drug within 30 days of randomization or have previously received any gene transfer therapy within 3 years of entering the study.