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Trial record 16 of 34 for:    stem cell peripheral arterial disease AND marrow

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

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ClinicalTrials.gov Identifier: NCT03042572
Recruitment Status : Not yet recruiting
First Posted : February 3, 2017
Last Update Posted : May 3, 2018
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Martin Teraa, MD, PhD, UMC Utrecht

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.


Condition or disease Intervention/treatment Phase
Peripheral Arterial Disease Cardiovascular Diseases Vascular Diseases Drug: Allogeneic Mesenchymal Stromal Cell Other: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : July 2021

Arm Intervention/treatment
Experimental: Allogeneic Mesenchymal Stromal Cell
Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
Drug: Allogeneic 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.
Other Names:
  • Allogeneic bone marrow-derived mesenchymal stromal cells
  • Allogeneic bone marrow-derived mesenchymal stem cells
  • Allogeneic BM-MSC

Placebo Comparator: Placebo
Intramuscular placebo injection
Other: Placebo
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.




Primary Outcome Measures :
  1. Therapy Success [ Time Frame: 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 Outcome Measures :
  1. Major amputation [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Amputation sited proximal from the ankle joint

  2. Minor amputation [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Amputation sited distal from the ankle joint

  3. Therapy Success [ Time Frame: 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.

  4. Mortality [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Mortality

  5. Ulcer healing [ Time Frame: 2 and 6 months ]
    Changes in the number and extent of leg ulcers,

  6. Changes in pain [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Resolution of rest pain and alteration in visual analogue pain (VAS) score

  7. Pain-free walking distance [ Time Frame: 2 and 6 months ]
    Changes in pain free walking distance (treadmill at 3 km/h without incline)

  8. Ankle-brachial index (ABI) [ Time Frame: 2 and 6 months ]
    Alterations in ankle-brachial index (ABI)

  9. Toe-brachial index (TBI) [ Time Frame: 2 and 6 months ]
    Alterations in toe-brachial index (TBI)

  10. Quality of life based on EuroQol 5D (EQ5D) questionnaire scores [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire

  11. Quality of life based on Short Form 36 (SF36) questionnaire scores [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations in quality of life assessed using Short Form 36 quality of life questionnaire

  12. Clinical status according to Fontaine classification [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations clinical status according to Fontaine classification

  13. Clinical status according to Rutherford classification [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations clinical status according to Rutherford classification


Other Outcome Measures:
  1. 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 [ Time Frame: 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).

  2. 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 [ Time Frame: 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).

  3. Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03042572


Contacts
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Contact: Joep GJ Wijnand, MD +31 88 755 9747 J.G.J.Wijnand-2@umcutrecht.nl
Contact: Martin Teraa, MD, PhD +31 88 755 6965 m.teraa@umcutrecht.nl

Locations
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Netherlands
University Medical Center Utrecht Not yet recruiting
Utrecht, Netherlands, 3508 GA
Contact: Joep GJ Wijnand, MD    +31 88 755 9747    J.G.J.Wijnand-2@umcutrecht.nl   
Contact: Martin Teraa, MD, PhD    +31 88 755 6965    m.teraa@umcutrecht.nl   
Sub-Investigator: Hendrik Gremmels, MD, PhD         
Sponsors and Collaborators
Martin Teraa, MD, PhD
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: Marianne C Verhaar, MD, PhD UMC Utrecht
Study Chair: Gert Jan de Borst, MD, PhD UMC Utrecht

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Martin Teraa, MD, PhD, Surgical Resident & Postdoc Physician, UMC Utrecht
ClinicalTrials.gov Identifier: NCT03042572     History of Changes
Other Study ID Numbers: NL59038.000.16
First Posted: February 3, 2017    Key Record Dates
Last Update Posted: May 3, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Martin Teraa, MD, PhD, UMC Utrecht:
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)
Additional relevant MeSH terms:
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Vascular Diseases
Peripheral Arterial Disease
Peripheral Vascular Diseases
Neovascularization, Pathologic
Cardiovascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Metaplasia
Pathologic Processes