Cardiovascular Diseases, Peripheral Arterial Disease, Vascular Diseases
Conditions
Keywords
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)
Brief summary
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.
Interventions
DRUGAllogeneic Mesenchymal Stromal Cell
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.
OTHERPlacebo
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.
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Martin Teraa, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Therapy Success | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in pain | 2, 6, 12, 24, and 60 months | Resolution of rest pain and alteration in visual analogue pain (VAS) score |
| Quality of life based on Short Form 36 (SF36) questionnaire scores | 2, 6, 12, 24, and 60 months | Alterations in quality of life assessed using Short Form 36 quality of life questionnaire |
| Clinical status according to Fontaine classification | 2, 6, 12, 24, and 60 months | Alterations clinical status according to Fontaine classification |
| Clinical status according to Rutherford classification | 2, 6, 12, 24, and 60 months | Alterations clinical status according to Rutherford classification |
| Major amputation | 2, 6, 12, 24, and 60 months | Amputation sited proximal from the ankle joint |
| Minor amputation | 2, 6, 12, 24, and 60 months | Amputation sited distal from the ankle joint |
| Therapy Success | 2, 6, 12, 24, and 60 months | 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. |
| Mortality | 2, 6, 12, 24, and 60 months | Mortality |
| Ulcer healing | 2 and 6 months | Changes in the number and extent of leg ulcers, |
| Pain-free walking distance | 2 and 6 months | Changes in pain free walking distance (treadmill at 3 km/h without incline) |
| Ankle-brachial index (ABI) | 2 and 6 months | Alterations in ankle-brachial index (ABI) |
| Toe-brachial index (TBI) | 2 and 6 months | Alterations in toe-brachial index (TBI) |
| Quality of life based on EuroQol 5D (EQ5D) questionnaire scores | 2, 6, 12, 24, and 60 months | Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect | 6 months | The investigators will use matrigel tubule forming assays using MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014). |
| Correlation of in-vitro angiogenic assay (Endothelial repair assay using a scratch wound assay using MSC-derived conditioned medium) of donor MSC with clinical effect | 6 months | The investigators will use endothelial repair assays using a scratch wound assay with MSC-derived conditioned medium to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (see Gremmels et al. Mol Ther. 2014). |
| Correlation of in-vitro angiogenic assay (Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient) of donor MSC with clinical effect | 6 months | The investigators will use Boyden chamber migration assays to test migration towards a platelet derived growth factor gradient in order to test angiogenic capacity of the batches of donor Mesenchymal Stromal Cells (MSC) and correlate these with the primary and secondary outcomes (et al. Mol Ther. 2014). |
Countries
Netherlands
Contacts
Primary ContactJoep GJ Wijnand, MD
Backup ContactMartin Teraa, MD, PhD
Outcome results
None listed