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

Primary Purpose

Peripheral Arterial Disease, Cardiovascular Diseases, Vascular Diseases

Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Allogeneic Mesenchymal Stromal Cell
Placebo
Sponsored by
Martin Teraa, MD, PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring 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)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University Medical Center Utrecht

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Allogeneic Mesenchymal Stromal Cell

Placebo

Arm Description

Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection

Intramuscular placebo injection

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Major amputation
Amputation sited proximal from the ankle joint
Minor amputation
Amputation sited distal from the ankle joint
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.
Mortality
Mortality
Ulcer healing
Changes in the number and extent of leg ulcers,
Changes in pain
Resolution of rest pain and alteration in visual analogue pain (VAS) score
Pain-free walking distance
Changes in pain free walking distance (treadmill at 3 km/h without incline)
Ankle-brachial index (ABI)
Alterations in ankle-brachial index (ABI)
Toe-brachial index (TBI)
Alterations in toe-brachial index (TBI)
Quality of life based on EuroQol 5D (EQ5D) questionnaire scores
Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire
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
Clinical status according to Fontaine classification
Alterations clinical status according to Fontaine classification
Clinical status according to Rutherford classification
Alterations clinical status according to Rutherford classification

Full Information

First Posted
January 27, 2017
Last Updated
May 2, 2018
Sponsor
Martin Teraa, MD, PhD
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT03042572
Brief Title
Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs
Acronym
SAIL
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

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Unknown status
Study Start Date
December 2018 (Anticipated)
Primary Completion Date
December 2020 (Anticipated)
Study Completion Date
July 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Martin Teraa, MD, PhD
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Allogeneic Mesenchymal Stromal Cell
Arm Type
Experimental
Arm Description
Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Intramuscular placebo injection
Intervention Type
Drug
Intervention Name(s)
Allogeneic Mesenchymal Stromal Cell
Other Intervention Name(s)
Allogeneic bone marrow-derived mesenchymal stromal cells, Allogeneic bone marrow-derived mesenchymal stem cells, Allogeneic BM-MSC
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
Therapy Success
Description
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Major amputation
Description
Amputation sited proximal from the ankle joint
Time Frame
2, 6, 12, 24, and 60 months
Title
Minor amputation
Description
Amputation sited distal from the ankle joint
Time Frame
2, 6, 12, 24, and 60 months
Title
Therapy Success
Description
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.
Time Frame
2, 6, 12, 24, and 60 months
Title
Mortality
Description
Mortality
Time Frame
2, 6, 12, 24, and 60 months
Title
Ulcer healing
Description
Changes in the number and extent of leg ulcers,
Time Frame
2 and 6 months
Title
Changes in pain
Description
Resolution of rest pain and alteration in visual analogue pain (VAS) score
Time Frame
2, 6, 12, 24, and 60 months
Title
Pain-free walking distance
Description
Changes in pain free walking distance (treadmill at 3 km/h without incline)
Time Frame
2 and 6 months
Title
Ankle-brachial index (ABI)
Description
Alterations in ankle-brachial index (ABI)
Time Frame
2 and 6 months
Title
Toe-brachial index (TBI)
Description
Alterations in toe-brachial index (TBI)
Time Frame
2 and 6 months
Title
Quality of life based on EuroQol 5D (EQ5D) questionnaire scores
Description
Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire
Time Frame
2, 6, 12, 24, and 60 months
Title
Quality of life based on Short Form 36 (SF36) questionnaire scores
Description
Alterations in quality of life assessed using Short Form 36 quality of life questionnaire
Time Frame
2, 6, 12, 24, and 60 months
Title
Clinical status according to Fontaine classification
Description
Alterations clinical status according to Fontaine classification
Time Frame
2, 6, 12, 24, and 60 months
Title
Clinical status according to Rutherford classification
Description
Alterations clinical status according to Rutherford classification
Time Frame
2, 6, 12, 24, and 60 months
Other Pre-specified Outcome Measures:
Title
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
Description
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).
Time Frame
6 months
Title
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
Description
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).
Time Frame
6 months
Title
Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect
Description
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).
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joep GJ Wijnand, MD
Phone
+31 88 755 9747
Email
J.G.J.Wijnand-2@umcutrecht.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Martin Teraa, MD, PhD
Phone
+31 88 755 6965
Email
m.teraa@umcutrecht.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne C Verhaar, MD, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gert Jan de Borst, MD, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Study Chair
Facility Information:
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3508 GA
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joep GJ Wijnand, MD
Phone
+31 88 755 9747
Email
J.G.J.Wijnand-2@umcutrecht.nl
First Name & Middle Initial & Last Name & Degree
Martin Teraa, MD, PhD
Phone
+31 88 755 6965
Email
m.teraa@umcutrecht.nl
First Name & Middle Initial & Last Name & Degree
Hendrik Gremmels, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.
Citations:
PubMed Identifier
25567765
Citation
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.
Results Reference
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PubMed Identifier
26460286
Citation
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.
Results Reference
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PubMed Identifier
23426345
Citation
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.
Results Reference
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PubMed Identifier
27612499
Citation
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.
Results Reference
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PubMed Identifier
26908409
Citation
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.
Results Reference
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PubMed Identifier
26511056
Citation
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.
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Citation
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PubMed Identifier
26148006
Citation
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.
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PubMed Identifier
25174586
Citation
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PubMed Identifier
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Citation
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.
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PubMed Identifier
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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.
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PubMed Identifier
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Citation
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.
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Results Reference
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Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs

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