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

NCT03042572 | Unknown Phase 2 DMC

• 1 other identifier: NL59038.000.16
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

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)

Outcome Measures

Primary Outcomes (1)

• 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.

  6 months

Secondary Outcomes (13)

• Major amputation

  2, 6, 12, 24, and 60 months

• Minor amputation

  2, 6, 12, 24, and 60 months

• Therapy Success

  2, 6, 12, 24, and 60 months

• Mortality

  2, 6, 12, 24, and 60 months

• Ulcer healing

  2 and 6 months

Other Outcomes (3)

• 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

• 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

• Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect

  6 months

Study Arms (2)

Allogeneic Mesenchymal Stromal Cell

EXPERIMENTAL

Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection

Drug: Allogeneic Mesenchymal Stromal Cell

Placebo

PLACEBO COMPARATOR

Intramuscular placebo injection

Other: Placebo

Interventions

Allogeneic Mesenchymal Stromal Cell DRUG

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.

Also known as: Allogeneic bone marrow-derived mesenchymal stromal cells, Allogeneic bone marrow-derived mesenchymal stem cells, Allogeneic BM-MSC

Allogeneic Mesenchymal Stromal Cell

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Martin Teraa, MD, PhD: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

University Medical Center Utrecht

Utrecht, 3508 GA, Netherlands

Location

Related Publications (18)

• Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, van der Graaf Y, Algra A, van der Tweel I, Doevendans PA, Mali WP, Moll FL, Verhaar MC. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation. 2015 Mar 10;131(10):851-60. doi: 10.1161/CIRCULATIONAHA.114.012913. Epub 2015 Jan 7.

  PMID: 25567765 BACKGROUND

• Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials. Eur J Vasc Endovasc Surg. 2015 Dec;50(6):775-83. doi: 10.1016/j.ejvs.2015.08.018. Epub 2015 Oct 12.

  PMID: 26460286 BACKGROUND

• Teraa M, Sprengers RW, van der Graaf Y, Peters CE, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013 Dec;258(6):922-9. doi: 10.1097/SLA.0b013e3182854cf1.

  PMID: 23426345 BACKGROUND

• Spreen MI, Gremmels H, Teraa M, Sprengers RW, Verhaar MC, Statius van Eps RG, de Vries JP, Mali WP, van Overhagen H; PADI and JUVENTAS Study Groups. Diabetes Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia: Pooled Data From Two Randomized Controlled Trials. Diabetes Care. 2016 Nov;39(11):2058-2064. doi: 10.2337/dc16-0850. Epub 2016 Sep 9.

  PMID: 27612499 BACKGROUND

• Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc. 2016 Feb 23;5(2):e002938. doi: 10.1161/JAHA.115.002938. No abstract available.

  PMID: 26908409 BACKGROUND

• Peeters Weem SM, Teraa M, den Ruijter HM, de Borst GJ, Verhaar MC, Moll FL. Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. 2016 Jan;51(1):83-9. doi: 10.1016/j.ejvs.2015.09.010. Epub 2015 Oct 26.

  PMID: 26511056 BACKGROUND

• Teraa M, Schutgens RE, Sprengers RW, Slaper-Cortenbach I, Moll FL, Verhaar MC; Juventas Study Group. Core diameter of bone marrow aspiration devices influences cell density of bone marrow aspirate in patients with severe peripheral artery disease. Cytotherapy. 2015 Dec;17(12):1807-12. doi: 10.1016/j.jcyt.2015.08.004. Epub 2015 Sep 28.

  PMID: 26428987 BACKGROUND

• Wisman PP, Teraa M, de Borst GJ, Verhaar MC, Roest M, Moll FL. Baseline Platelet Activation and Reactivity in Patients with Critical Limb Ischemia. PLoS One. 2015 Jul 6;10(7):e0131356. doi: 10.1371/journal.pone.0131356. eCollection 2015.

  PMID: 26148006 BACKGROUND

• Gremmels H, Teraa M, Quax PH, den Ouden K, Fledderus JO, Verhaar MC. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther. 2014 Nov;22(11):1960-70. doi: 10.1038/mt.2014.161. Epub 2014 Sep 1.

  PMID: 25174586 BACKGROUND

• Gremmels H, Fledderus JO, Teraa M, Verhaar MC. Mesenchymal stromal cells for the treatment of critical limb ischemia: context and perspective. Stem Cell Res Ther. 2013;4(6):140. doi: 10.1186/scrt351.

  PMID: 24246031 BACKGROUND

• Teraa M, Fledderus JO, Rozbeh RI, Leguit RJ, Verhaar MC; Juventas Study Groupdagger. Bone marrow microvascular and neuropathic alterations in patients with critical limb ischemia. Circ Res. 2014 Jan 17;114(2):311-4. doi: 10.1161/CIRCRESAHA.114.302791. Epub 2013 Nov 11.

  PMID: 24218170 BACKGROUND

• Niemansburg SL, Teraa M, Hesam H, van Delden JJ, Verhaar MC, Bredenoord AL. Stem cell trials for cardiovascular medicine: ethical rationale. Tissue Eng Part A. 2014 Oct;20(19-20):2567-74. doi: 10.1089/ten.TEA.2013.0332. Epub 2013 Dec 11.

  PMID: 24164351 BACKGROUND

• Westerweel PE, Teraa M, Rafii S, Jaspers JE, White IA, Hooper AT, Doevendans PA, Verhaar MC. Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus. PLoS One. 2013;8(3):e60357. doi: 10.1371/journal.pone.0060357. Epub 2013 Mar 28.

  PMID: 23555959 BACKGROUND

• Teraa M, Sprengers RW, Westerweel PE, Gremmels H, Goumans MJ, Teerlink T, Moll FL, Verhaar MC; JUVENTAS study group. Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients. PLoS One. 2013;8(1):e55592. doi: 10.1371/journal.pone.0055592. Epub 2013 Jan 31.

  PMID: 23383236 BACKGROUND

• Setacci C, de Donato G, Teraa M, Moll FL, Ricco JB, Becker F, Robert-Ebadi H, Cao P, Eckstein HH, De Rango P, Diehm N, Schmidli J, Dick F, Davies AH, Lepantalo M, Apelqvist J. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg. 2011 Dec;42 Suppl 2:S43-59. doi: 10.1016/S1078-5884(11)60014-2.

  PMID: 22172473 BACKGROUND

• Sprengers RW, Teraa M, Moll FL, de Wit GA, van der Graaf Y, Verhaar MC; JUVENTAS Study Group; SMART Study Group. Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment. J Vasc Surg. 2010 Oct;52(4):843-9, 849.e1. doi: 10.1016/j.jvs.2010.04.057.

  PMID: 20598482 BACKGROUND

• Sprengers RW, Moll FL, Teraa M, Verhaar MC; JUVENTAS Study Group. Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. J Vasc Surg. 2010 Jun;51(6):1564-8. doi: 10.1016/j.jvs.2010.02.020.

  PMID: 20488328 BACKGROUND

• Wijnand JGJ, Teraa M, Gremmels H, van Rhijn-Brouwer FCC, de Borst GJ, Verhaar MC; SAIL Study Group. Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia. J Vasc Surg. 2018 Feb;67(2):656-661. doi: 10.1016/j.jvs.2017.09.026. Epub 2017 Dec 11.

  PMID: 29242062 DERIVED

MeSH Terms

Conditions

Peripheral Arterial Disease; Cardiovascular Diseases; Vascular Diseases; Chronic Limb-Threatening Ischemia; Peripheral Arterial Occlusive Disease 1

Condition Hierarchy (Ancestors)

Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ischemia

Study Officials

• Marianne C Verhaar, MD, PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Gert Jan de Borst, MD, PhD

  UMC Utrecht

  STUDY CHAIR

Central Study Contacts

Joep GJ Wijnand, MD

CONTACT

+31 88 755 9747; J.G.J.Wijnand-2@umcutrecht.nl

Martin Teraa, MD, PhD

CONTACT

+31 88 755 6965; m.teraa@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Surgical Resident & Postdoc Physician

Study Record Dates

• First Submitted: January 27, 2017
• First Posted: February 3, 2017
• Study Start: December 1, 2018
• Primary Completion: December 1, 2020
• Study Completion: July 1, 2021
• Last Updated: May 3, 2018

Record last verified: 2018-05

Locations

NL (1)