The Efficacy and Safety of REX-001 to Treat Ischemic Rest Pain in Subjects With CLI Rutherford Category 4 and DM

Study Overview
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Brief Summary
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This trial is a pivotal, placebo-controlled, double-blind, parallel-group, adaptive trial conducted in subjects with DM and CLI Rutherford Category 4. 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.

Official Title
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The Efficacy and Safety of Intra-arterial Administration of REX-001 to Treat Ischemic Rest Pain in Subjects With Critical Limb Ischemia (CLI) Rutherford Category 4 and Diabetes Mellitus (DM): a Pivotal, Placebo-controlled, Double-blind, Parallel-group, Adaptive Trial

Conditions
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Peripheral Arterial Disease (PAD), Diabetes Mellitus (DM), Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Cardiovascular Disease, Critical Limb Ischemia (CLI)

Intervention / Treatment
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* Drug: REX-001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 to ≤ 85 years. Diagnosis of Type I or II DM, established more than one year ago. Glycosylated hemoglobin (HbA1c) < 9%. Subjects with poor or no (surgical or endovascular) revascularization option classified as CLI Rutherford Category 4. The blood circulation in these subjects must be compromised at screening, defined as: Ankle systolic pressure < 50 mm Hg, or Toe systolic pressure < 30 mm Hg, or TcpO2 < 30 mm Hg, and Flat or barely pulsatile ankle or metatarsal PVR 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. Women of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) must have a negative pregnancy test at screening. 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. Exclusion Criteria: 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. CLI Rutherford Category 5. Uncontrolled or untreated proliferative retinopathy. Failed surgical or endovascular revascularization on the index leg within 10 days after the procedure. 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). 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. At screening, the presence of only neuropathic ulcers on the index leg. Amputation at or above the talus on the index leg. Planned major amputation within the first month after randomization. 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. Blood clotting disorder not caused by medication (e.g., thrombophilia). Severe hypertension according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. A platelet count < 50,000/ μL. International normalised 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. Evidence of moderate to severe hepatocellular dysfunction according to the treating physician. Positive test for human immunodeficiency virus 1 (HIV 1), HIV 2, hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum. 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. Subjects who participate in another clinical interventional trial. Subjects who have been treated with experimental medication within 30 days of screening. Subjects who were treated with other cell therapies for CLI within the last 12 months preceding the screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REX-001<br>REX-001 is a cell suspension of autologous BM-MNCs composed of several mature cell types. | Drug: REX-001<br>* REX-001 is administered through an intra-arterial catheter.<br>|
| Placebo Comparator: Placebo<br>The final formulation of the placebo will be a diluted suspension of red blood cells. | Drug: Placebo<br>* Placebo is administered through an intra-arterial catheter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete relief of ischemic rest pain without developing ischemic lesions on the index leg. | Change in Rutherford classification from CLI Category 4 to Category 3 or lower 12 months after administration of REX-001 or placebo. | The primary endpoint for this trial will be assessed at 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous, Angiogenesis, Bone Marrow-derived Mononuclear Cells (BM-MNCs), Advanced Therapy Medicinal Product (ATMP), Tissue-engineered Medicinal Product, Revascularization, Vasculogenesis, Arteriogenesis