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Intra-arterial Stem Cell Therapy for Patients With Chronic Limb Ischemia (CLI)

NCT ID: NCT00371371

Last Updated: 2012-12-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

160 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-09-30

Study Completion Date

2012-12-31

Brief Summary

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The purposes of this study are to determine whether intra-arterial injection of autologous stem cells is effective in the treatment of chronic limb ischemia (CLI), to characterize stem cell dysfunction in patients with CLI, and to relate the stem cell function with clinical outcome.

Detailed Description

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Despite advances in surgical and radiological vascular techniques, a significant number of patients with chronic critical limb ischaemia (CLI) are not eligible for revascularization procedures, often leaving amputation as the only option. Consequently, exploring new strategies for revascularization of ischemic limbs is of major importance. Preclinical studies and pioneering clinical trials suggest that administration of bone marrow (BM) mononuclear cells (MNC) into ischemic limbs enhances neovascularization, improves tissue perfusion and prevents amputation. However, no definite proof is available as the clinical studies thus far have been small and lacked double-blinded controls.

JUVENTAS is a randomized, double-blinded placebo-controlled trial in 109 - 160 patients with CLI to investigate the potential clinical effects of repeated intra-arterial infusion of BM-MNC in these patients (the exact number of patients to be included cannot be specified in advance because of the planned group sequential interim analyses). In addition, it will study the functional characteristics of the BM-MNC obtained from CLI patients and relate BM-MNC dysfunction to clinical outcome.

Conditions

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Peripheral Vascular Diseases Arterial Occlusive Diseases Leg Ulcer Gangrene Ischemia

Keywords

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clinical trial chronic critical limb ischemia leg pain cell therapy bone marrow mononuclear progenitor cell stem cell critical limb ischemia nonhealing leg ulcer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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BM-MNC

autologous bone marrow-derived mononuclear cells

Group Type EXPERIMENTAL

Bone marrow punction

Intervention Type PROCEDURE

A total volume of 100 ml bone marrow will be aspirated from the iliac crest under local anaesthesia (lidocaine) according to local routine. To maximise the patients comfort, 5-10 mg midazolam and 50 ug fentanyl will be administered intravenously.

BM-MNC infusion

Intervention Type PROCEDURE

Repeated intra-arterial infusion of autologous BM-MNC into the common femoral artery

Placebo

Placebo

Group Type PLACEBO_COMPARATOR

Bone marrow punction

Intervention Type PROCEDURE

A total volume of 100 ml bone marrow will be aspirated from the iliac crest under local anaesthesia (lidocaine) according to local routine. To maximise the patients comfort, 5-10 mg midazolam and 50 ug fentanyl will be administered intravenously.

Placebo infusion

Intervention Type PROCEDURE

Repeated intra-arterial infusion of placebo (PBS/4% HAS/heparin, coloured with autologous erythrocytes to match the colour of BM-MNC suspension) into the common femoral artery.

Interventions

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Bone marrow punction

A total volume of 100 ml bone marrow will be aspirated from the iliac crest under local anaesthesia (lidocaine) according to local routine. To maximise the patients comfort, 5-10 mg midazolam and 50 ug fentanyl will be administered intravenously.

Intervention Type PROCEDURE

BM-MNC infusion

Repeated intra-arterial infusion of autologous BM-MNC into the common femoral artery

Intervention Type PROCEDURE

Placebo infusion

Repeated intra-arterial infusion of placebo (PBS/4% HAS/heparin, coloured with autologous erythrocytes to match the colour of BM-MNC suspension) into the common femoral artery.

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

* Age \> 18 years
* Severe infra-popliteal peripheral arterial occlusive disease \[PAOD\] (Fontaine class IIb, III or IV)
* Invalidating intermittent claudication, persistent, recurring rest pain requiring analgesia and/or non-healing ulcers present for \> 4 weeks without evidence of improvement in response to conventional therapies
* Ankle brachial index \< 0.6 or "unreliable"
* Not eligible for surgical or radiological 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
* Anticipated inability to obtain 100 ml of bone marrow aspirate
* Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus
* Follow-up impossible
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Catharijne Foundation

UNKNOWN

Sponsor Role collaborator

UMC Utrecht

OTHER

Sponsor Role lead

Responsible Party

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R.W. Sprengers, MD, PhD

Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Frans L Moll, MD, PhD

Role: STUDY_CHAIR

UMC Utrecht

Marianne C Verhaar, MD, PhD

Role: STUDY_DIRECTOR

UMC Utrecht

Ralf W Sprengers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Martin Teraa, MD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Locations

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University Medical Center Utrecht (UMC Utrecht)

Utrecht, , Netherlands

Site Status

Countries

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Netherlands

References

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Sprengers RW, Lips DJ, Moll FL, Verhaar MC. Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann Surg. 2008 Mar;247(3):411-20. doi: 10.1097/SLA.0b013e318153fdcb.

Reference Type BACKGROUND
PMID: 18376183 (View on PubMed)

Sprengers RW, Janssen KJ, Moll FL, Verhaar MC, van der Graaf Y; SMART Study Group. Prediction rule for cardiovascular events and mortality in peripheral arterial disease patients: data from the prospective Second Manifestations of ARTerial disease (SMART) cohort study. J Vasc Surg. 2009 Dec;50(6):1369-76. doi: 10.1016/j.jvs.2009.07.095. Epub 2009 Oct 17.

Reference Type BACKGROUND
PMID: 19837547 (View on PubMed)

Sprengers RW, Moll FL, Verhaar MC. Stem cell therapy in PAD. Eur J Vasc Endovasc Surg. 2010 Mar;39 Suppl 1:S38-43. doi: 10.1016/j.ejvs.2009.12.001. Epub 2010 Feb 12.

Reference Type BACKGROUND
PMID: 20153223 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20488328 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20598482 (View on PubMed)

Moazzami B, Mohammadpour Z, Zabala ZE, Farokhi E, Roohi A, Dolmatova E, Moazzami K. Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev. 2022 Jul 8;7(7):CD008347. doi: 10.1002/14651858.CD008347.pub4.

Reference Type DERIVED
PMID: 35802393 (View on PubMed)

Hanssen NMJ, Teraa M, Scheijen JLJM, Van de Waarenburg M, Gremmels H, Stehouwer CDA, Verhaar MC, Schalkwijk CG. Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes. Diabetes Care. 2021 Jan;44(1):157-163. doi: 10.2337/dc20-0581. Epub 2020 Nov 3.

Reference Type DERIVED
PMID: 33144352 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26428987 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26148006 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25567765 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24218170 (View on PubMed)

Other Identifiers

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06/030

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

CS 06.007

Identifier Type: -

Identifier Source: secondary_id

JUVENTAS

Identifier Type: -

Identifier Source: org_study_id