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

Martin Teraa, MD, PhD60 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Peripheral Arterial Disease Cardiovascular Diseases

Interventions

Allogeneic Mesenchymal Stromal CellDRUG

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.

PlaceboOTHER

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 6 months

Secondary Outcomes

Major amputation

Amputation sited proximal from the ankle joint

Time frame: 2, 6, 12, 24, and 60 months

Minor amputation

Amputation sited distal from the ankle joint

Time frame: 2, 6, 12, 24, and 60 months

Therapy Success

Time frame: 2, 6, 12, 24, and 60 months

Mortality

Time frame: 2, 6, 12, 24, and 60 months

Ulcer healing

Changes in the number and extent of leg ulcers,

Time frame: 2 and 6 months

Changes in pain

Resolution of rest pain and alteration in visual analogue pain (VAS) score

Time frame: 2, 6, 12, 24, and 60 months

Pain-free walking distance

Changes in pain free walking distance (treadmill at 3 km/h without incline)

Time frame: 2 and 6 months

Ankle-brachial index (ABI)

Alterations in ankle-brachial index (ABI)

Time frame: 2 and 6 months

Toe-brachial index (TBI)

Alterations in toe-brachial index (TBI)

Time frame: 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

Time frame: 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

Time frame: 2, 6, 12, 24, and 60 months

Clinical status according to Fontaine classification

Alterations clinical status according to Fontaine classification

Time frame: 2, 6, 12, 24, and 60 months

Clinical status according to Rutherford classification

Alterations clinical status according to Rutherford classification

Time frame: 2, 6, 12, 24, and 60 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts