Double blind randomized autologous stem cell trial treatment for peripheral arterial disease (PAD) with critical limb threatening ischemia

Peripheral vascular disease and Critical Limb Ischemia (CLI; also referred to as chronic limb threatening ischemia, CLTI) disease are caused by partial or complete blockage of blood vessels in the lower limbs. As the disease progresses, subjects deteriorate, and the limbs is subsequently impaired due to decreased blood flow in the small and microscopic blood vessels. Since the limbs do not receive sufficient blood supply, there is deterioration in limb function and wounds and lesions begin to form that will not heal. When further deterioration occurs, amputation may be required. This trial uses your own blood-derived stem and progenitor cells in a single treatment session in order to restore blood flow to the limb, heal wounds and prevent the need for amputation of the leg.

Inclusion: Male or female patients who fulfil the following criteria will be eligible in this study:

1. Have the time and ability to complete the study and comply with instructions.

2. Capable of understanding of the purpose of the study and the contents of the informed consent form.

3. Aged at least 18 years.

4. Non-pregnant and non-lactating female patients.

5. Have the clinical indications diagnostic of CLI based on Rutherford category 4-5

6. Have at least one of the hemodynamic indicators of severe peripheral arterial occlusive disease (WIfI ischemia grade 2):

• Toe pressure < 40 mmHg

• Ankle pressure < 70 mmHg

• TcPO2 < 40mmHg

7. Meeting one of the following conditions:

a. Poor candidate for standard revascularization treatment for peripheral arterial disease due to unfavorable anatomy or high surgical/intervention risk based on the patient’s underlying comorbidities.

b. After undergoing clinically ineffective revascularization. Six weeks or more after undergoing a prior index limb revascularization the patient demonstrates:

• No improvement in clinical signs and symptoms of CLI as evidenced by lack of improvement in rest pain (when not under increased pain relief) and/or inadequate wound healing or progression of tissue loss despite adequate standard treatment.

• Ongoing ischemia as defined above in the criterion 6.

• The patient is no longer amenable to further interventional or surgical revascularization (see inclusion criterion 7).

Exclusion: Patients who fulfil any of the following criteria, at the moment of screening or enrolment, will not be eligible in this study.

1. Severe and uncorrected aorto-iliac and/or common femoral artery disease, i.e. absence of femoral pulse or monophasic common femoral artery doppler waveform.

2. Concurrent therapy that, in the Investigator's opinion, would interfere with the evaluation of the feasibility of the study medication.

3. Treatment with any investigational product within the last 6 months or enrollment in any active study involving the use of investigational devices or drugs.

4. Presence of any other condition or circumstance that, in the judgment of the investigator, might negatively impact the outcomes of the treatment under investigation.

5. Prognosis of a major amputation (below or above the knee), within 4 weeks after screening.

6. Severe wound (WIfI wound grade 2 or 3).

7. Significant ongoing infection (WIfI infection grade 2 or 3).

8. Relative or absolute contraindications for intramuscular injections at the intended treatment site, in cases such as severe skin lesions, severe edema or morbid obesity, based on clinician opinion.

9. Blood transfusions during the preceding 4 weeks (to exclude the potential of non-autologous cells in the harvested blood).

10. Heart failure (New York Heart Association [NYHA] 3-4).

11. Patient suffering from active vasculitis.

12. Hemoglobin (Hb) less than 9 g/dL.

13. Patient with HbA1C > 8.5%

14. Myocardial infarction, brain infarction, uncontrolled myocardial ischemia or persistent severe heart failure (ejection fraction [EF] < 25%) during the preceding 3 months.

15. Significant valvular disease or valve replacement (based on medical record).

16. Renal failure(estimated glomerular filtration rate[eGFR]<30 mL/min/1.73 m2, chronic kidney damage stage 4-5).

17. Liver failure, Model for End-stage Liver Disease (MELD) scores 15 and higher.

18. Liver function tests more than three times normal upper limit (normal limits being defined in each local laboratory)(glutamic-oxaloacetic transaminase [GOT], glutamic-pyruvic transaminase [GPT], alkaline phosphatase [AlkP], gamma- glutamyl transferase [GGT], lactate dehydrogenase [LDH]).

19. Abnormal coagulation tests when not under warfarin (normalized prothrombin time [PT INR] >2).

20. Pregnant or lactating women at entry of study.

21. People who are unwilling to agree to use acceptable methods of contraception during the study.

22. Malignancy within the preceding 3 years, except basal cell carcinoma.

23. Concurrent acute infectious disease with septicemia

24. Chronic infectious disease (human immunodeficiency virus-1 [HIV-1], human immunodeficiency virus-2 [HIV-2], hepatitis B virus [HBV], hepatitis C virus [HCV]).

25. Immunodeficiency syndrome.

26. Raynaud’s syndrome

27. Systemic treatment with cytotoxic and/or immunosuppressive treatment.

28. Inability to communicate (that may interfere with the clinical evaluation of the patient).

29. Patient unlikely to be available for follow-up.