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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

Tracking Information
First Submitted Date  ICMJE January 27, 2017
First Posted Date  ICMJE February 3, 2017
Last Update Posted Date May 3, 2018
Estimated Study Start Date  ICMJE December 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 1, 2017)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03042572 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2017)
  • Major amputation [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Amputation sited proximal from the ankle joint
  • Minor amputation [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Amputation sited distal from the ankle joint
  • 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.
  • Mortality [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Mortality
  • Ulcer healing [ Time Frame: 2 and 6 months ]
    Changes in the number and extent of leg ulcers,
  • Changes in pain [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Resolution of rest pain and alteration in visual analogue pain (VAS) score
  • Pain-free walking distance [ Time Frame: 2 and 6 months ]
    Changes in pain free walking distance (treadmill at 3 km/h without incline)
  • Ankle-brachial index (ABI) [ Time Frame: 2 and 6 months ]
    Alterations in ankle-brachial index (ABI)
  • Toe-brachial index (TBI) [ Time Frame: 2 and 6 months ]
    Alterations in toe-brachial index (TBI)
  • 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
  • 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
  • Clinical status according to Fontaine classification [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations clinical status according to Fontaine classification
  • Clinical status according to Rutherford classification [ Time Frame: 2, 6, 12, 24, and 60 months ]
    Alterations clinical status according to Rutherford classification
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 1, 2017)
  • 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).
  • 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).
  • 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).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs
Official Title  ICMJE Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Peripheral Arterial Disease
  • Cardiovascular Diseases
  • Vascular Diseases
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: Allogeneic Mesenchymal Stromal Cell
    Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
    Intervention: Drug: Allogeneic Mesenchymal Stromal Cell
  • Placebo Comparator: Placebo
    Intramuscular placebo injection
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: February 1, 2017)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03042572
Other Study ID Numbers  ICMJE NL59038.000.16
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.
Responsible Party Martin Teraa, MD, PhD, UMC Utrecht
Study Sponsor  ICMJE Martin Teraa, MD, PhD
Collaborators  ICMJE ZonMw: The Netherlands Organisation for Health Research and Development
Investigators  ICMJE
Principal Investigator: Marianne C Verhaar, MD, PhD UMC Utrecht
Study Chair: Gert Jan de Borst, MD, PhD UMC Utrecht
PRS Account UMC Utrecht
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP