Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs (SAIL)
2018年5月2日 更新者：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.
調査の概要
研究の種類
介入
入学 (予想される)
60
段階
- フェーズ2
- フェーズ 3
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Utrecht、オランダ、3508 GA
- University Medical Center Utrecht
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年歳以上 (大人、高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
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.
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：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.
他の名前：
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プラセボコンパレーター：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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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Therapy Success
時間枠：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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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Major amputation
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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)
時間枠：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)
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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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
時間枠：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
時間枠：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
時間枠：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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協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
スポンサー
捜査官
- 主任研究者：Marianne C Verhaar, MD, PhD、UMC Utrecht
- スタディチェア：Gert Jan de Borst, MD, PhD、UMC Utrecht
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- 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.
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (予想される)
2018年12月1日
一次修了 (予想される)
2020年12月1日
研究の完了 (予想される)
2021年7月1日
試験登録日
最初に提出
2017年1月27日
QC基準を満たした最初の提出物
2017年2月1日
最初の投稿 (見積もり)
2017年2月3日
学習記録の更新
投稿された最後の更新 (実際)
2018年5月3日
QC基準を満たした最後の更新が送信されました
2018年5月2日
最終確認日
2018年5月1日
詳しくは
本研究に関する用語
キーワード
その他の研究ID番号
- NL59038.000.16
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
未定
IPD プランの説明
Study outcomes will be published in international peer-reviewed journals and individual participant data (IPD) will become available on request.
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米国FDA規制医薬品の研究
いいえ
米国FDA規制機器製品の研究
いいえ
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