Please select the eligibility criteria that correspond to the clinical trial below.
Title: Critical Limb Ischemia Treatment by Local Intra-Muscular Injection of Autologous Mononuclear Cells
Brief Summary: The primary focus of the trial is safety and efficacy of the intra-muscular implantation of either bone-marrow, or peripheral blood mononuclear cells, in critical limb ischemia, as judged by the proportion of patients which are alive without major amputation 6 months after inclusion.


Options:
A: Inclusion Criteria:

1. Patients with atherosclerotic peripheral artery disease with classic claudication (exercise-induced pain, cramps, fatigue, or other equivalent discomfort involving large muscle groups of the leg(s) that is consistently relieved by rest) or atypical leg pain (exertional leg pain that does not begin at rest or does not resolve consistently with rest) as defined by the San Diego Claudication Questionnaire.
2. Age ≥40 years
3. Resting ankle-brachial index \<0.90 or a resting toe-brachial index of \<0.70 at baseline testing
4. Presence of significant stenosis or occlusion of infrainguinal arteries including the superficial femoral artery, popliteal artery and/or infrapopliteal arteries as determined by: Duplex ultrasound imaging (occlusion or focal doubling of peak systolic velocity of one or more affected segments) OR lower extremity computed Tomography Angiography (CTA) OR lower extremity magnetic resonance angiography (MRA) OR lower extremity catheter-based contrast arteriography. Each of these noninvasive and invasive anatomic assessments will identify patients with at least a 50% stenosis in the affected segment.

Exclusion Criteria:

1. Presence of any musculoskeletal disease, cardiac or pulmonary disease, or neurological disease that limits the patient's ability to walk to fulfill protocol requirements (claudication must be the consistent primary exercise limitation)
2. Inability to complete treadmill testing per protocol requirements.
3. Ability to walk for more than 12 minutes on the treadmill during treadmill testing.
4. Patients who identify both legs as equivocally symptomatic or alternate between symptomatic legs on the baseline treadmill tests.
5. Patients with critical limb ischemia (ischemic rest pain or ischemia-related non healing wounds or tissue loss (Rutherford categories 4-6).
6. Recent (\<3 months) infrainguinal revascularization (surgery or endovascular revascularization) or revascularization planned during study period
7. Patients with a patent infrainguinal bypass graft in the index limb, with or without evidence of a hemodynamically significant stenosis or other defect (kinking, pseudoaneurysm, or fistula). Patients with an occluded infrainguinal bypass graft or a patent aortobifemoral or femoral-femoral bypass graft are NOT excluded.
8. Patients with \>2+ lower extremity pitting edema
9. Patients with myelodysplastic syndrome (MDS)
10. Patients who are pregnant or lactating, planning to become pregnant in the next 12 months, or are unwilling to use acceptable forms of birth control during study participation.
11. Congestive Heart Failure hospitalization within the last 1 month prior to enrollment
12. Acute coronary syndrome in the last 1 month prior to enrollment
13. Human Immunodeficiency Virus positive, active Hepatitis B Virus or Hepatitis C Virus Disease
14. History of cancer within the last 5 years, except basal cell skin carcinoma
15. Any bleeding diathesis defined as an International Normalized Ratio ≥ 2.0 (off anticoagulation therapy) or history of platelet count less than 100,000 or hemophilia
16. Contraindication to magnetic resonance imaging (MRI) (including knee/tibial/fibular replacement hardware in the index leg) or known allergy to MRI contrast media
17. Chronic kidney disease \[effective Glomerular Filtration Rate \<30 by modification of diet in renal disease (MDRD) or Mayo or Cockcroft-Gault formula\]
18. Uncontrolled diabetes \[Hemoglobin A1C (HbA1C)\>8.5\]
19. Planned change to (initiate or terminate) active involvement in a supervised exercise program (e.g., with a trainer, exercise protocol, and goals, such as in a peripheral arterial disease, cardiac or pulmonary rehabilitation program) during study participation
20. Plans to change medical therapy during the duration of the study, (i.e. patients who use cilostazol should remain on a stable dose for four weeks prior to enrollment and should not change doses for the 6 months of the study duration.) As always, cilostazol can be discontinued if new heart failure or intolerance occurs during study participation.
21. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata).
22. History of inflammatory or progressively fibrotic conditions (e.g. rheumatoid arthritis, systemic lupus erythematosis, vasculitic disorders, idiopathic pulmonary fibrosis, retroperitoneal fibrosis).
23. Patients with any untreated stenosis \> 70% of the distal aorta, common iliac, or external iliac arteries by CT, Angiography or MRI imaging will be excluded from enrollment (patients with previously successfully revascularized inflow stenoses may enroll in PACE). Subjects who were screen failures for a flow-limiting proximal lesion may be rescreened 3 months after successful angioplasty/stenting.
24. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted)
25. Concurrent enrollment in another clinical interventional investigative trial.
26. Presence of any clinical condition that in the opinion of the principal Investigator or the sponsor makes the patient not suitable to participate in the trial
B: 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
C: Inclusion Criteria:

* Males or females with non-child bearing potential in the age group of 18-60 yrs of Indian origin.
* Established CLI, clinically and hemodynamically confirmed as per Rutherford- II-4, III-5, or III-6; Patients having Infra-inguinal arterial occlusive disease with rest pain or ischemic ulcer/necrosis, who are not eligible for or have failed traditional revascularization treatment (No option patients)
* Ankle Brachial Pressure Index (ABPI) ≤ 0.6 or ankle pressure ≤ 70 mm Hg or TcPO2 ≤ 60 mmHg in the foot
* Patients if having associated Type II Diabetes, should be on medication and well controlled (HbA1c ≤ 8%) without complications
* Patients who are able to understand the requirements of the study, and willing to provide voluntary written informed consent, abide by the study requirements, and agree to return for required follow-up visits
* Normal liver and renal function
* On regular medication for hypertension if any

Exclusion Criteria:

* Patients with CLI suitable for surgical or percutaneous revascularization as determined by the surgeon performing vascular procedure and patients with any acute/chronic inflammatory condition
* CLI patient requiring amputation proximal to trans-metatarsal level
* Patients with gait disturbance for reasons other than CLI.
* Type I diabetes
* Patients having respiratory complications/left ventricular ejection fraction \< 25%f) Stroke or myocardial infarction within last 3 months
* Patients who are contraindicated for MRA
* Have clinically serious and/or unstable inter-current infection, medical illnesses or conditions that are uncontrolled or whose control, in the opinion of the Investigator, may be jeopardized by participation in this study or by the complications of this therapy
* Documented terminal illness or cancer or any concomitant disease process with a life expectancy of less than 1 year
* Patients already enrolled in another investigational drug trial or completed within 3 months.
* History of severe alcohol or drug abuse within 3 months of screening.
* Hb% \< 10 gm%, Serum Creatinine ≥ 2mg%, Serum Total Bilirubin ≥2mg%, HbA1c \> 8%
* Women with child bearing potential, pregnant and lactating women.
* Patients tested positive for HIV 1, HCV, HBV,
D: Inclusion Criteria:

* Patients with unilateral critical chronic limb ischemia but not suitable candidates for non-surgical or surgical revascularization
* Before being included, the patient must be screened for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, treponema pallidum

Exclusion Criteria:

* Buerger disease
* Ischemic ulcers with infectious symptoms
* Diabetes mellitus with HbA1c \> 7,5% or with proliferative retinopathy
* Past or current malignancy
* Contra-indication to general anaesthesia
* Chronic haemodialysis
* Prothrombin Time \< 60%,
* Recent onset (within 3 months) of myocardial infarction or brain infarction
* Coronary angioplasty within 1 year
* Atrial fibrillation, mechanical mitral prosthetic valve
* Unexplained hematological abnormality.
* Expected life span less than six months
* Patient not competent to give informed consent

Answer: D