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

Ischemia Clinical Trial

— JUVENTAS  

Official title:

Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Patients With Chronic Critical Limb Ischemia: a Randomized, Placebo-controlled Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00371371
• Other study ID #: JUVENTAS
• Secondary ID: 06/030CS 06.007
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 1, 2006
• Last updated: December 12, 2012
• Start date: September 2006
• Est. completion date: December 2012

Study information

• Verified date: December 2012
• Source: UMC Utrecht
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arterial Occlusive Diseases
• Gangrene
• Ischemia
• Leg Ulcer
• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Vascular Diseases

Intervention

Procedure:
• 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.
• BM-MNC infusion
Repeated intra-arterial infusion of autologous BM-MNC into the common femoral artery
• 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.

Locations

Country	Name	City	State
Netherlands	University Medical Center Utrecht (UMC Utrecht)	Utrecht

Sponsors (2)

Lead Sponsor	Collaborator
UMC Utrecht	Catharijne Foundation

Country where clinical trial is conducted

Netherlands, 

References & Publications (5)

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Amputation-free survival		six months	No
Other	Treatment failure	Composite endpoint defined as major amputation of treated leg, all-cause mortality, doubling in total wound surface area, or de novo gangrene	six months	No
Other	Successfull treatment	Composite endpoint defined as subject is (A) alive, (B) without major amputation of index limb, (C) not worsened rutherford class or VAS, and (D) improved in either Rutherford or VAS (>30mm)	six months	No
Primary	major amputation		six months	Yes
Secondary	minor amputation		six months	Yes
Secondary	number and extent of leg ulcers		six months	No
Secondary	resolvement of rest pain		six months	No
Secondary	improvement of ankle-brachial index (ABI)		six months	No
Secondary	improvement transcutaneous oxygen pressure (TcpO2)		six months	No
Secondary	changes in quality of life		suix months	No
Secondary	changes in clinical status (Rutherford classification)		six months	No