Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia
Condition: Critical Limb Ischemia
MeSH terms: Chronic Limb-Threatening Ischemia; Ischemia
Intervention: HGF Plasmid (AMG0001); Matching Placebo
Intervention description: IM; IM
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 46.0
Sex: All
Minimum age: 40 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: CLI

Summary:

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

Eligibility criteria:

        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.