Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase I/II Study of Regenerative Cell Therapy in Treating Diabetic Patients With Critical Limb Ischemia
Brief Summary: The aim of this study is to assess the efficacy and safety of autologous transplantation of bone-marrow cells for therapeutic angiogenesis and vasculogenesis in diabetic patients with non-revascularizable critical limb ischemia.


Options:
A: Inclusion Criteria:

* Age \> 18 years
* Severe Peripheral Artery Disease (PAD; Fontaine class III and / or IV):

  * Fontaine III (Rutherford 4): persistent, recurring rest pain requiring analgesia
  * Fontaine IV (Rutherford 5): non-healing ulcers present for \> 4 weeks without evidence of improvement in response to conventional therapies
* Ankle brachial index \< 0.6 or unreliable (non-compressible or not in proportion to the Fontaine classification)
* Not eligible for surgical or endovascular revascularization
* Written informed consent.

Exclusion Criteria:

* History of neoplasm or malignancy in the past 10 years
* Serious known concomitant disease with life expectancy of less than one year
* Rutherford 6 in which amputation on the short term (within 1-2 weeks) is inevitable
* Pregnancy or unwillingness to use adequate contraception during study
* Uncontrolled acute or chronic infection with systemic symptoms
* Follow-up impossible.
B: Inclusion Criteria:

* Patients 18 years of age or greater with atherosclerotic vascular disease that is viewed as not readily amenable to reconstructive surgery and Rutherford Category 4 ischemia (ischemic rest pain) and Rutherford Category 5 ischemia (ulceration or tissue necrosis) and by the judgment of their referring physician are not reasonable candidates for revascularization options of either percutaneous balloon angioplasty or a surgical revascularization.
* Objective evidence of severe peripheral arterial disease will include an ankle brachial index (ABI) of less than 0.5, or, in the case of patients who have vessels calcified and thereby "non-compressible" vessels metatarsal pulse volume recording (PVR) that is flat or barely pulsatile in the diseased limb on two consecutive examinations performed at least one week apart.
* Patients competent to give informed consent.
* No active malignant disease that could involve the bone marrow, or history of treatment of malignant disease that could have damaged the bone marrow.
* Before being accepted for the study the patient must be screened for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human transmissible spongiform encephalopathy, including Creutzfeldt-Jacob Disease, Treponema pallidum, and have a negative standard infectious disease panel including a CMV PCR test.
* Patients who are hemodynamically stable.

Exclusion Criteria:

* Patients with poorly controlled diabetes mellitus (HbA1C \> 8%)
* Patients with renal insufficiency (creatinine \> 2.5).
* Patients with evidence of infectious disease as determined by e. above or other medical findings.
* Pregnant women (women capable of childbearing must have a negative pregnancy test).
* Patients with cognitive impairments.
* Other comorbid disease that would be expected to result in less than one year life expectancy
* Past malignancy or history of chemotherapy or radiation affecting the bone marrow.
* History of inflammatory or progressively fibrotic conditions: .e.g., rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis
* Infection as evidenced by WBC count of \>15,000 and/or temperature \>38 degrees C. Large area of cellulitis in the afflicted limb that in the opinion of the investigators would require the institution of antibiotics OR evidence of osteomyelitis corroborated by radiographic or scintigraphic examination
* Cardiovascular conditions:

  * Exercise limiting angina ( Canadian Cardiovascular Society Class 3 (Appendix 7);
  * Congestive heart failure (New York Heart Association class 3 (Appendix 5);
  * Unstable angina;
  * Acute ST elevation myocardial infarction (MI) within 1month;
  * Transient ischemic attack or stroke within 1 month;
  * Severe valvular disease
* Patients with any history of organ transplants;
C: Inclusion Criteria:

* Diabetic patients under treatment (type I or II)
* Critical limb ischemia (rest pain and/or non-healing ischemic ulcers lasting more than 4 weeks, and/or Ankle-Brachial Index \< 0,8)
* Not suitable to be revascularized (surgical and interventional consensus)

Exclusion Criteria:

* Neoplastic disease and/or hematologic disease during the last 2 years
* Diabetic retinopathy
* Ischemic ulcer greater than 10 cm2
* Major amputation at target limb
* Life expectancy \> 2 years
D: Inclusion Criteria:

* History of exercise-limiting intermittent claudication and peripheral arterial disease with symptoms in one or both legs, of at least 2 months duration with no change in symptom severity in the 2 months prior to screening.
* A Doppler-measured ankle-brachial index (ABI) of ≤0.80 or toe-brachial index (TBI) of \<0.70 in at least one leg after 10 minutes of rest.
* Limitation in walking secondary to claudication with a mean peak walking time (PWT) of between 1 and 10 minutes on a standardized Gardner protocol for exercise treadmill test (ETT).
* Angiographic or equivalent anatomic evidence (MRA) of arterial occlusive disease (\>70%) in the distal common femoral artery or superficial femoral artery and its branches of at least one leg within 12 months prior to screening.
* Postmenopausal (females),surgically sterile, or use adequate birth control.

Exclusion Criteria:

* Presence of significant inflow disease \[defined as \>50% stenosis\] in the distal aorta, common or external iliac as assessed by conventional angiogram, digital subtraction angiography (DSA), or magnetic resonance angiography (MRA) performed \< 1 year prior to screening.
* Critical limb ischemia, either chronic or acute ischemia manifested by rest pain, ulceration, or gangrene (Category 4 through 6 of Society for Vascular Surgery \[SVS\] classification \[Rutherford\]).
* History of malignant neoplasm (except curable non-melanoma skin malignancies).
* Renal failure (serum creatinine \>2.0 mg/dL) or end-stage renal disease(requiring hemodialysis or renal replacement therapy).
* Significant hepatic disease (\>3-fold elevation in ALT/AST).
* HBV or HCV carriers.
* Severe pulmonary disease (e.g. severe chronic obstructive pulmonary disease).
* Subjects with Acute Stroke within 6 months prior to screening.
* Subjects with uncontrolled diabetes mellitus.
* Specific ophthalmologic conditions that preclude retinal photography,vascular lesions of the anterior segment of the eye, proliferative retinopathy, age-related macular degeneration or intra-ocular surgery within 6 months prior to enrollment.
* Gross obesity (BMI≥40).
* Buerger's disease or other forms of inflammatory arteritis.
* Class IV congestive heart failure, as defined by the New York Heart Association or a myocardial infarction within 6 months prior to screening.
* Subject with deep vein thrombosis within 3 months prior to screening.
* Inability to complete the standardized treadmill protocol for reasons other than claudication including symptoms such as angina, dyspnea, joint pains, or excessive fatigue.
* Percutaneous intervention or surgical revascularization in the index lower limb within 6 months prior to enrollment.
* Heart angioplasty with or without stent or coronary bypass surgery within the past 6 months.
* Participation in a structured exercise treatment protocol within 30 days prior to screen testing.
* Subject is planning to participate in a structured exercise treatment protocol during the 180 days following administration of the investigational product.
* Participation in a previous gene transfer trial in which the subject received active investigational product (placebo subjects are eligible).
* Concurrent or prior participation in another clinical trial within 30 days prior to screen testing.
* Chronic use of Cox-2 inhibitors, defined as subjects needing daily use of the agent for more than 30 days prior to screening.
* Subject is taking any of the following drugs for life-threatening conditions or as part of a life-sustaining treatment: Cyclosporine (Sandimmune®),Systemic androgens/anabolic steroids, systemic corticosteroids.
* History of bleeding diathesis (e.g. hemophilia due to Factor VIII or IX deficiency).
* Pregnancy or breast-feeding.
* Uncontrolled hypertension or significant hypotension.
* Immunodeficiency states (e.g, current HIV positivity, or organ transplant recipient) or subject receiving immunosuppressive medications.
* Alcohol or other substance abuse.

Answer: C