Arterial Occlusive Diseases, Gangrene, Ischemia, Leg Ulcer, Peripheral Vascular Diseases
Conditions
Keywords
clinical trial, chronic critical limb ischemia, leg pain, cell therapy, bone marrow, mononuclear, progenitor cell, stem cell, critical limb ischemia, nonhealing leg ulcer
Brief 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.
Detailed 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.
Interventions
PROCEDUREBone 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.
PROCEDUREBM-MNC infusion
Repeated intra-arterial infusion of autologous BM-MNC into the common femoral artery
PROCEDUREPlacebo 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.
Sponsors
Catharijne Foundation
UMC Utrecht
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| major amputation | six months |
Secondary
| Measure | Time frame |
|---|---|
| resolvement of rest pain | six months |
| improvement transcutaneous oxygen pressure (TcpO2) | six months |
| changes in quality of life | suix months |
| changes in clinical status (Rutherford classification) | six months |
| minor amputation | six months |
| number and extent of leg ulcers | six months |
| improvement of ankle-brachial index (ABI) | six months |
Other
| Measure | Time frame | Description |
|---|---|---|
| Successfull treatment | six months | 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) |
| Amputation-free survival | six months | — |
| Treatment failure | six months | Composite endpoint defined as major amputation of treated leg, all-cause mortality, doubling in total wound surface area, or de novo gangrene |
Countries
Netherlands
Outcome results
None listed