Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs

Study Overview
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Brief Summary
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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.

Official Title
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Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial

Conditions
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Peripheral Arterial Disease, Cardiovascular Diseases, Vascular Diseases

Intervention / Treatment
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* Drug: Allogeneic Mesenchymal Stromal Cell
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Allogeneic Mesenchymal Stromal Cell<br>Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection | Drug: Allogeneic Mesenchymal Stromal Cell<br>* Intramuscular allogeneic BM-MSC injection: MSCs will be extracted from BM of healthy volunteers, expanded with human platelet lysate, and stored. Patients will receive intramuscular allogeneic BM-MSC injections at 30 sites in the lower leg of the ischemic limb. Blinded syringes are provided and cell suspensions will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL containing 5*10^6 MSC per site; total 150*10^6 BM-MSCs) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.<br>* Other names: Allogeneic BM-MSC;|
| Placebo Comparator: Placebo<br>Intramuscular placebo injection | Other: Placebo<br>* Intramuscular placebo injections. Patients will receive intramuscular placebo injections at 30 prespecified sites in the lower leg of the ischemic limb. Blinded syringes are provided and will be injected intramuscularly by an experienced operator into multiple sites (30 sites, 1-1.5cm in depth, volume of 1.0mL placebo per site) in the ischemic lower extremity. Injections will be performed under IV analgesia (fentanyl) and sedation (midazolam) if necessary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapy Success | Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a success a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major amputation | Amputation sited proximal from the ankle joint | 2, 6, 12, 24, and 60 months | 
| Minor amputation | Amputation sited distal from the ankle joint | 2, 6, 12, 24, and 60 months | 
| Therapy Success | Composite outcome measure considering mortality, limb status, clinical classification and changes in pain score. To be a success a subject must: A, be alive; B, be without a major amputation on the index limb; C, have not worsened in Rutherford classification or visual analog pain scale; and D, have improved in either Rutherford classification or visual analog pain scale. Subjects not meeting all of the criteria are classified as failures. | 2, 6, 12, 24, and 60 months | 
| Mortality | Mortality | 2, 6, 12, 24, and 60 months | 
| Ulcer healing | Changes in the number and extent of leg ulcers, | 2 and 6 months | 
| Changes in pain | Resolution of rest pain and alteration in visual analogue pain (VAS) score | 2, 6, 12, 24, and 60 months | 
| Pain-free walking distance | Changes in pain free walking distance (treadmill at 3 km/h without incline) | 2 and 6 months | 
| Ankle-brachial index (ABI) | Alterations in ankle-brachial index (ABI) | 2 and 6 months | 
| Toe-brachial index (TBI) | Alterations in toe-brachial index (TBI) | 2 and 6 months | 
| Quality of life based on EuroQol 5D (EQ5D) questionnaire scores | Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire | 2, 6, 12, 24, and 60 months | 
| Quality of life based on Short Form 36 (SF36) questionnaire scores | Alterations in quality of life assessed using Short Form 36 quality of life questionnaire | 2, 6, 12, 24, and 60 months | 
| Clinical status according to Fontaine classification | Alterations clinical status according to Fontaine classification | 2, 6, 12, 24, and 60 months | 
| Clinical status according to Rutherford classification | Alterations clinical status according to Rutherford classification | 2, 6, 12, 24, and 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Critical Limb Ischemia (CLI), Severe Limb Ischemia (SLI), Peripheral Artery Disease (PAD), Peripheral Artery Occlusive Disease (PAOD), Cardiovascular disease, Mesenchymal stromal cell (MSC), Mesenchymal stem cell (MSC)