Please select the eligibility criteria that correspond to the clinical trial below.
Title: Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial
Brief Summary: The primary objective of this trial is to investigate whether intramuscular administration of allogeneic mesenchymal stromal cells (MSC) is safe and potentially effective, assessed as a composite outcome of mortality, limb status, clinical status (Rutherford classification) and pain score (visual analogue scale), in patients with no-option severe limb ischemia (SLI).

The investigators will conduct a double-blind, placebo-controlled randomized clinical trial to investigate the effect of allogeneic bone marrow(BM)-derived MSC in patients with SLI, who are not eligible for conventional surgical or endovascular therapies. The investigators intend to include 60 patients, who will be randomized to undergo 30 intramuscular injections with either BM-MSC (30 injection sites with 5\*10\^6 MSCs each) or placebo in the lower leg of the ischemic extremity. Primary outcome i.e. therapy success, a composite outcome considering mortality, limb status, clinical status (Rutherford classification) and changes in pain score, will be assessed at six months.


Options:
A: Inclusion Criteria:

* Chronic severe CLI patients fulfilling all the following criteria are considered suitable for inclusion in the study.

  1. At least 6 months since the onset of CLI (Chronic peripheral artery disease or Buerger disease)
  2. Patients with luminal stenosis \> 50% by leg angiography
  3. Age is between 20 and 80.
  4. Patients whose Rutherford's class is II-4, III-5, or III-6（Patients with rest pain or ischemic ulcer/necrosis)
  5. Patients for whom angioplasty and bypass surgery are not indicated because of anatomical or procedural reasons or frequent reocclusion/ restenosis following the traditional revascularization (No option patients)
  6. Patients who can give informed consent themselves in writing.

Exclusion Criteria:

* Any one of the following exclusion criteria is sufficient to disqualify a patient from the study.

  1. Left ventricular ejection fraction \< 25%
  2. Patients with a history of severe allergic reactions or side effects to G-CSF preparations or apheresis.
  3. Less than 6 months since last episode of myocardial/cerebral infarction.
  4. Patients with unstable angina, with a treatment rating of 3 in the Braunwald system, but a severity of III and a clinical rating of B or C.
  5. Patients with diabetic proliferating retinopathy (new Fukuda classification BI to BV).
  6. Patients with malignant tumor
  7. Patients with chronic rheumatoid arthritis.
  8. Patients with hematological disease (leukemia, myeloproliferative disease, or myelodysplastic syndromes).
  9. Patients currently suffering from or having a history of interstitial pneumonitis.
  10. Patients for whom cranial MRA reveals cerebral aneurysm.
  11. Patients for whom abdominal CT or ultrasonography reveals splenomegaly.
  12. Patients with cirrhosis of the liver.
  13. Patients who cannot discontinue Warfarin.
  14. Leukocytes less than 4,000/µL or exceeding 10,000/µL.
  15. Platelets less than 100,000/µL.
  16. Hemoglobin less than 10 g/dL.
  17. AST (GOT) exceeding 100 IU/L or ALT (GPT) exceeding 100 IU/L.
  18. Patients with severe neural disorder in their legs.
  19. Patients with gait disturbance for reasons other than CLI (such as sciatic neuralgia, or vasculitis), making exercise tolerance evaluation on a treadmill with stress ECG difficult.
  20. Pregnant or nursing patients, those who may be pregnant, or those who plan on becoming pregnant before the end of the study period.
  21. Any other reason that the Clinical Supervisors or Clinical Researchers may have for considering a case unsuitable for the study.
B: Inclusion Criteria:

1. Be ≥ 40 and ≤90 years of age.
2. Patients requiring lower extremity major amputation, as determined by an independent vascular specialist.
3. If ulceration or gangrene present, it is distal to malleoli (to allow adequate length of ATM area of approximately 3cm x 10cm x 3 cm)
4. Amputation can safely be performed up to 30 days after screening, as determined by an independent vascular or orthopedic surgeon.
5. Females of childbearing potential must be willing to use one form of birth control for the duration of the study. Female participants must undergo a blood or urine pregnancy test at screening.

Exclusion Criteria:

1. Patients who are pregnant, planning to become pregnant in the next 12 months, or lactating.
2. CHF hospitalization within the last 1 month prior to enrollment.\*
3. Acute coronary syndrome in the last 1 month prior to enrollment.\*
4. HIV positive, or active, untreated HCV as determined by review of medical records.
5. History of cancer within the last 5 years, except basal cell skin carcinoma
6. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted).
7. Concurrent enrollment in another clinical investigative trial that may alter the outcomes of enrollment in this trial.
8. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata).
9. Presence of any clinical condition that in the opinion of the PI or the sponsor makes the patient not suitable to participate in the trial.

   * As defined by the standard definitions of CHF and ACS by the American Heart Association.
C: Inclusion Criteria:

* Patients with PAOD (Stage III or IV)
* Distal arterial occlusions
* Patients with Buergers Disease
* Signed informed consent

Exclusion Criteria:

* Successful bypass operation or intervention within the last 3 months
* Active infection, feber, chronic inflammatory disease
* HIV, Hepatitis
* Tumor within the last 5 years, complete remission required
* Stroke or myocardial infarction within last 3 months
* Renal insufficiency (creatinine \> 2 mg/dl)
* Liver disease (GOT \> 2x upper limit oder spontaneous INR \> 1,5).
* Anemia (hemoglobin \< \<10 mg/dl)
* Thrombocytopenia \< 100.000/µl
* Allergies to Aspirin, Clopidogrel, Heparin
* Bleeding disorder
* Gastrointestinal bleeding within last 3 months
* Surgery or trauma within the last 2 months
* Pregnancy
* Mental retardation
* Inclusion in other clinical study within last 30 days
D: 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.

Answer: D