The Efficacy and Safety of REX-001 to Treat Ischemic Ulcers in Subjects With CLI Rutherford Category 5 and DM

INCLUSION CRITERIA:

1. Aged ≥ 18 to ≤ 85 years.
2. Diagnosis of Type I or II DM, established more than one year ago.
3. Glycosylated hemoglobin (HbA1c) < 9%.
4. Subjects with poor or no (surgical or endovascular) revascularization optionclassified as CLI Rutherford Category 5. For these patients, one of the following mustbe confirmed and documented at screening:

• Ankle systolic pressure < 70 mmHg, or
• Toe systolic pressure < 50 mmHg, or
• TcpO2 < 30 mmHg (lying down). Subjects with non-compressible or calcified vesselsmust qualify on toe pressure or tcpO2. Poor or no revascularization option means that, in the opinion of the Investigator,revascularization using surgical or endovascular methods are not feasible due to forexample the anatomy of existing vessels and/or existing comorbidity and/or previouslyfailed surgical or endovascular revascularization.

5. In the opinion of the Investigator, the subject is controlled on medical therapyindicated for CLI (unless there is a documented contraindication or intolerance) andpain management is optimized.
6. Women of childbearing potential must have a negative pregnancy test at screening. Awoman is considered of childbearing potential, i.e. fertile, following menarche anduntil becoming post-menopausal unless permanently sterile. Permanent sterilisationmethods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Apostmenopausal state is defined as no menses for 12 months without an alternativemedical cause. Men and women who are sexually active shall use effective contraceptivemethods for the duration of their participation in this study if the partner of themale participant, or if the female participant is of childbearing potential. Effectivecontraceptive methods are e.g.:

• Combined (estrogen and progestogen containing) hormonal contraception associatedwith inhibition of ovulation (oral, intravaginal or transdermal),
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable),
• Intrauterine device (IUD),
• Intrauterine hormone-releasing system (IUS),
• Bilateral tubal occlusion,
• Vasectomised partner, or
• Sexual abstinence. The use of this contraceptive method should be continued forat least the duration of participation in the study, and should be continuedthereafter as long as indicated by the study doctor.

EXCLUSION CRITERIA: Subjects meeting any of the following criteria must not be enrolled in the trial:

1. Advanced CLI defined as presence of major tissue loss as significantulceration/gangrene proximal to the metatarsal heads (CLI Rutherford Category 6).Significant ulceration/gangrene means any ulceration that extends beyond thesubcutaneous tissue layer, or any gangrene or tissue necrosis proximal to themetatarsal heads.
2. CLI Rutherford Category 4.
3. Uncontrolled or untreated proliferative retinopathy.
4. Failed surgical or endovascular revascularization on the index leg within 10 daysafter the procedure.
5. Subjects in whom arterial insufficiency in the lower extremity is the result of acutelimb ischemia or an immunological or inflammatory or non-atherosclerotic disorder (e.g., thromboangiitis obliterans (Buerger's Disease), systemic sclerosis (bothlimited and diffuse forms).
6. Clinical evidence of invasive infection on index leg defined as major tissue loss atthe mid-foot or heel involving tendon and/or bone, and/or when intravenous antibioticsare required to treat the infection according to the Investigator.
7. At screening, the presence of only neuropathic ulcers on the index leg.
8. Amputation at or above the talus on the index leg.
9. Planned major amputation within the first month after randomization.
10. On the index leg, use of concomitant wound treatments not currently approved forischemic wound-healing within 30 days prior to screening or plans to initiate new,nonstandard-of-care treatments to the index leg during the trial.
11. Blood clotting disorder not caused by medication (e.g., thrombophilia).
12. Severe hypertension according to the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure. (34)
13. A platelet count < 50,000/μL.
14. International normalized ratio (INR) > 1.5. For patients on anticoagulant medicationan INR > 1.5 is allowed, provided that the Investigator and the haematologist considerthe patient eligible to collect BM.
15. Evidence of moderate to severe hepatocellular dysfunction according to the treatingphysician.
16. Positive test for human immunodeficiency virus 1 (HIV 1), HIV 2, hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum.
17. Subjects who may not be healthy enough to successfully complete all protocolrequirements including BM collection, or who are not expected to survive more than 12months, or in whom results may be particularly difficult to assess, as assessed by theInvestigator. For example:
18. Concurrent severe congestive heart failure (New York Heart Association ClassesIII and IV).
19. Life-threatening ventricular arrhythmias, unstable angina (characterized byincreasingly frequent episodes with modest exertion or at rest, worseningseverity, and prolonged duration), and/or myocardial infarction within four weeksbefore screening.
20. Coronary artery bypass grafting or percutaneous coronary intervention within onemonth before screening.
21. A renal and/or carotid revascularization procedure within one month of screening.
22. Transient ischemic attack within three months prior to screening.
23. Deep vein thrombosis within three months prior to screening.
24. Subjects with immunocompromised conditions, organ transplant recipients and/orsubjects in need of immunosuppressive therapy.
25. Neurological dementia (i.e., Alzheimer's Disease).
26. Subjects who participate in another clinical interventional trial.
27. Subjects who have been treated with experimental medication within 30 days ofscreening.
28. Subjects who participated in other cell therapy trials for CLI.