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

The Efficacy and Safety of Intra-arterial Administration of REX-001 to Treat Ischemic Ulcers in Subjects With Critical Limb Ischemia (CLI) Rutherford Category 5 and Diabetes Mellitus: A Pivotal, Placebo-controlled, Double-blind, Parallel-group, Adaptive Trial

This trial is a pivotal, placebo-controlled, double-blind, parallel-group, adaptive trial conducted in subjects with DM and CLI Rutherford Category 5. Minimisation will be used to assign eligible subjects in a 2:1 ratio to receive a single intra-arterial administration of REX-001 or matching placebo into the index limb.

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 option classified as CLI Rutherford Category 5. For these patients, one of the following must be 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 vessels must 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 for example the anatomy of existing vessels and/or existing comorbidity and/or previously failed surgical or endovascular revascularization.

5. In the opinion of the Investigator, the subject is controlled on medical therapy indicated for CLI (unless there is a documented contraindication or intolerance) and pain management is optimized.

6. Women of childbearing potential must have a negative pregnancy test at screening. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Men and women who are sexually active shall use effective contraceptive methods for the duration of their participation in this study if the partner of the male participant, or if the female participant is of childbearing potential. Effective contraceptive methods are e.g.:

   • Combined (estrogen and progestogen containing) hormonal contraception associated with 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 for at least the duration of participation in the study, and should be continued thereafter 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 significant ulceration/gangrene proximal to the metatarsal heads (CLI Rutherford Category 6). Significant ulceration/gangrene means any ulceration that extends beyond the subcutaneous tissue layer, or any gangrene or tissue necrosis proximal to the metatarsal heads.

2. CLI Rutherford Category 4.

3. Uncontrolled or untreated proliferative retinopathy.

4. Failed surgical or endovascular revascularization on the index leg within 10 days after the procedure.

5. Subjects in whom arterial insufficiency in the lower extremity is the result of acute limb ischemia or an immunological or inflammatory or non-atherosclerotic disorder (e.g., thromboangiitis obliterans (Buerger's Disease), systemic sclerosis (both limited and diffuse forms).

6. Clinical evidence of invasive infection on index leg defined as major tissue loss at the mid-foot or heel involving tendon and/or bone, and/or when intravenous antibiotics are 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 for ischemic 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 medication an INR > 1.5 is allowed, provided that the Investigator and the haematologist consider the patient eligible to collect BM.

15. Evidence of moderate to severe hepatocellular dysfunction according to the treating physician.

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 protocol requirements including BM collection, or who are not expected to survive more than 12 months, or in whom results may be particularly difficult to assess, as assessed by the Investigator. For example:

    1. Concurrent severe congestive heart failure (New York Heart Association Classes III and IV).
    2. Life-threatening ventricular arrhythmias, unstable angina (characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged duration), and/or myocardial infarction within four weeks before screening.
    3. Coronary artery bypass grafting or percutaneous coronary intervention within one month before screening.
    4. A renal and/or carotid revascularization procedure within one month of screening.
    5. Transient ischemic attack within three months prior to screening.
    6. Deep vein thrombosis within three months prior to screening.
    7. Subjects with immunocompromised conditions, organ transplant recipients and/or subjects in need of immunosuppressive therapy.
    8. Neurological dementia (i.e., Alzheimer's Disease).

18. Subjects who participate in another clinical interventional trial.

19. Subjects who have been treated with experimental medication within 30 days of screening.

20. Subjects who participated in other cell therapy trials for CLI.