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Peripheral Arterial DiseasePhase 2/3SAILNCT03042572

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

A Phase 2/3 study testing Allogeneic Mesenchymal Stromal Cell in people with Peripheral Arterial Disease and Cardiovascular Diseases, run by Martin Teraa, MD, PhD at 1 site in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Allogeneic Mesenchymal Stromal Cell
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
1 siteNetherlands
Study dates
Dec 2018to Jul 2021
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

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

Netherlands1 site

  • University Medical Center Utrecht

    Utrecht, 3508 GA

    Joep GJ Wijnand, MD, +31 88 755 9747, J.G.J.Wijnand-2@umcutrecht.nl

    Martin Teraa, MD, PhD, +31 88 755 6965, m.teraa@umcutrecht.nl

Other trials in Netherlands

About this study

Official title: Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial

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.

Being tested
Allogeneic Mesenchymal Stromal Cell, Placebo
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)
Medical subject headings
Peripheral Arterial Disease, Cardiovascular Diseases, Vascular Diseases, Chronic Limb-Threatening Ischemia, Peripheral Arterial Occlusive Disease 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Allogeneic Mesenchymal Stromal CellDrug

    Also called Allogeneic bone marrow-derived mesenchymal stromal cells, Allogeneic bone marrow-derived mesenchymal stem cells, Allogeneic BM-MSC

    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.

  • PlaceboOther

    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 groups in NCT03042572
Study groupRoleWhat they receive
Allogeneic Mesenchymal Stromal CellExperimentalIntramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
Receives: Drug: Allogeneic Mesenchymal Stromal Cell
PlaceboPlacebo comparatorIntramuscular placebo injection
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 6 months

Secondary outcomes (13)

  1. Major amputation

    Amputation sited proximal from the ankle joint

    Measured: 2, 6, 12, 24, and 60 months

  2. Minor amputation

    Amputation sited distal from the ankle joint

    Measured: 2, 6, 12, 24, and 60 months

  3. 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.

    Measured: 2, 6, 12, 24, and 60 months

  4. Mortality

    Mortality

    Measured: 2, 6, 12, 24, and 60 months

  5. Ulcer healing

    Changes in the number and extent of leg ulcers,

    Measured: 2 and 6 months

  6. Changes in pain

    Resolution of rest pain and alteration in visual analogue pain (VAS) score

    Measured: 2, 6, 12, 24, and 60 months

  7. Pain-free walking distance

    Changes in pain free walking distance (treadmill at 3 km/h without incline)

    Measured: 2 and 6 months

  8. Ankle-brachial index (ABI)

    Alterations in ankle-brachial index (ABI)

    Measured: 2 and 6 months

  9. Toe-brachial index (TBI)

    Alterations in toe-brachial index (TBI)

    Measured: 2 and 6 months

  10. Quality of life based on EuroQol 5D (EQ5D) questionnaire scores

    Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire

    Measured: 2, 6, 12, 24, and 60 months

  11. Quality of life based on Short Form 36 (SF36) questionnaire scores

    Alterations in quality of life assessed using Short Form 36 quality of life questionnaire

    Measured: 2, 6, 12, 24, and 60 months

  12. Clinical status according to Fontaine classification

    Alterations clinical status according to Fontaine classification

    Measured: 2, 6, 12, 24, and 60 months

  13. Clinical status according to Rutherford classification

    Alterations clinical status according to Rutherford classification

    Measured: 2, 6, 12, 24, and 60 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Feb 2017 (estimated)
  2. Study startDec 2018 (estimated)
  3. Primary completionDec 2020 (estimated)
  4. Study completionJul 2021 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03042572
Sponsor's protocol ID
NL59038.000.16
Acronym
SAIL
Status last verified
May 2018
First submitted
27 Jan 2017
Last updated
3 May 2018
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.

Publications

  • 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.

    PubMed 25567765

  • 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.

    PubMed 26460286

  • 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.

    PubMed 23426345

  • 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.

    PubMed 27612499

  • 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.

    PubMed 26908409

  • 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.

    PubMed 26511056

  • 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.

    PubMed 26428987

  • 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.

    PubMed 26148006

  • 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.

    PubMed 25174586

  • 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.

    PubMed 24246031

  • 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.

    PubMed 24218170

  • 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.

    PubMed 24164351

  • 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.

    PubMed 23555959

  • 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.

    PubMed 23383236

  • 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.

    PubMed 22172473

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Allogeneic Mesenchymal Stromal Cell in people with Peripheral Arterial Disease and Cardiovascular Diseases, run by Martin Teraa, MD, PhD at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 3 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Joep GJ Wijnand, MD (+31 88 755 9747, J.G.J.Wijnand-2@umcutrecht.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Therapy Success (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03042572, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2018; AzTrials last refreshed its copy on 7 Nov 2026.

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