Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs (SAIL)
2018년 5월 2일 업데이트: Martin Teraa, MD, PhD
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.
연구 개요
연구 유형
중재적
등록 (예상)
60
단계
- 2 단계
- 3단계
연락처 및 위치
이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.
연구 장소
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Utrecht, 네덜란드, 3508 GA
- University Medical Center Utrecht
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참여기준
연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.
자격 기준
공부할 수 있는 나이
18년 이상 (성인, 고령자)
건강한 자원 봉사자를 받아들입니다
아니
연구 대상 성별
모두
설명
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.
공부 계획
이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 네 배로
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: Allogeneic Mesenchymal Stromal Cell
Intramuscular Allogeneic Bone marrow-derived Mesenchymal Stromal Cell Injection
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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.
다른 이름들:
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위약 비교기: Placebo
Intramuscular placebo injection
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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.
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Therapy Success
기간: 6 months
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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.
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6 months
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Major amputation
기간: 2, 6, 12, 24, and 60 months
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Amputation sited proximal from the ankle joint
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2, 6, 12, 24, and 60 months
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Minor amputation
기간: 2, 6, 12, 24, and 60 months
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Amputation sited distal from the ankle joint
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2, 6, 12, 24, and 60 months
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Therapy Success
기간: 2, 6, 12, 24, and 60 months
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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.
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2, 6, 12, 24, and 60 months
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Mortality
기간: 2, 6, 12, 24, and 60 months
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Mortality
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2, 6, 12, 24, and 60 months
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Ulcer healing
기간: 2 and 6 months
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Changes in the number and extent of leg ulcers,
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2 and 6 months
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Changes in pain
기간: 2, 6, 12, 24, and 60 months
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Resolution of rest pain and alteration in visual analogue pain (VAS) score
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2, 6, 12, 24, and 60 months
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Pain-free walking distance
기간: 2 and 6 months
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Changes in pain free walking distance (treadmill at 3 km/h without incline)
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2 and 6 months
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Ankle-brachial index (ABI)
기간: 2 and 6 months
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Alterations in ankle-brachial index (ABI)
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2 and 6 months
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Toe-brachial index (TBI)
기간: 2 and 6 months
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Alterations in toe-brachial index (TBI)
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2 and 6 months
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Quality of life based on EuroQol 5D (EQ5D) questionnaire scores
기간: 2, 6, 12, 24, and 60 months
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Alterations in quality of life assessed using EuroQoL 5D quality of life questionnaire
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2, 6, 12, 24, and 60 months
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Quality of life based on Short Form 36 (SF36) questionnaire scores
기간: 2, 6, 12, 24, and 60 months
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Alterations in quality of life assessed using Short Form 36 quality of life questionnaire
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2, 6, 12, 24, and 60 months
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Clinical status according to Fontaine classification
기간: 2, 6, 12, 24, and 60 months
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Alterations clinical status according to Fontaine classification
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2, 6, 12, 24, and 60 months
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Clinical status according to Rutherford classification
기간: 2, 6, 12, 24, and 60 months
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Alterations clinical status according to Rutherford classification
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2, 6, 12, 24, and 60 months
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기타 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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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
기간: 6 months
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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).
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6 months
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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
기간: 6 months
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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).
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6 months
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Correlation of in-vitro angiogenic assay (Matrigel tubule forming assay) of donor MSC with clinical effect
기간: 6 months
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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).
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6 months
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공동 작업자 및 조사자
여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.
수사관
- 수석 연구원: Marianne C Verhaar, MD, PhD, UMC Utrecht
- 연구 의자: Gert Jan de Borst, MD, PhD, UMC Utrecht
간행물 및 유용한 링크
연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.
일반 간행물
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
연구 기록 날짜
이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.
연구 주요 날짜
연구 시작 (예상)
2018년 12월 1일
기본 완료 (예상)
2020년 12월 1일
연구 완료 (예상)
2021년 7월 1일
연구 등록 날짜
최초 제출
2017년 1월 27일
QC 기준을 충족하는 최초 제출
2017년 2월 1일
처음 게시됨 (추정)
2017년 2월 3일
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
2018년 5월 3일
QC 기준을 충족하는 마지막 업데이트 제출
2018년 5월 2일
마지막으로 확인됨
2018년 5월 1일
추가 정보
이 연구와 관련된 용어
키워드
기타 연구 ID 번호
- NL59038.000.16
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
미정
IPD 계획 설명
Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
아니
미국 FDA 규제 기기 제품 연구
아니
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .