Clinical trial NCT03042572: Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs
Official title: Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Peripheral Arterial Disease
Cardiovascular Diseases
Vascular Diseases
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)
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2017-02-03
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Therapy Success
timeFrame: 6 months
Secondary outcomes:
measure: Major amputation
timeFrame: 2, 6, 12, 24, and 60 months
measure: Minor amputation
timeFrame: 2, 6, 12, 24, and 60 months
measure: Therapy Success
timeFrame: 2, 6, 12, 24, and 60 months
measure: Mortality
timeFrame: 2, 6, 12, 24, and 60 months
measure: Ulcer healing
timeFrame: 2 and 6 months
measure: Changes in pain
timeFrame: 2, 6, 12, 24, and 60 months
measure: Pain-free walking distance
timeFrame: 2 and 6 months
measure: Ankle-brachial index (ABI)
timeFrame: 2 and 6 months
measure: Toe-brachial index (TBI)
timeFrame: 2 and 6 months
measure: Quality of life based on EuroQol 5D (EQ5D) questionnaire scores
timeFrame: 2, 6, 12, 24, and 60 months
measure: Quality of life based on Short Form 36 (SF36) questionnaire scores
timeFrame: 2, 6, 12, 24, and 60 months
measure: Clinical status according to Fontaine classification
timeFrame: 2, 6, 12, 24, and 60 months
measure: Clinical status according to Rutherford classification
timeFrame: 2, 6, 12, 24, and 60 months
Other outcomes:
measure: 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
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect
timeFrame: 6 months
Locations:
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: Marianne C Verhaar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Gert Jan de Borst, MD, PhD
role: STUDY_CHAIR
References:
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