Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia: The Randomized, Double-Blind, Placebo-Controlled JUVENTAS Trial
Background—Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow (BM)-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of BM mononuclear cells (BMMNC) in patients with severe, non-revascularizable limb ischemia can prevent major amputation.
Methods and Results—The Juventas-trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, non-revascularizable limb ischemia. Patients were randomized to repetitive (3x; 3-weeks interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, i.e. major amputation at 6 months, with major amputation rates of 19% in the BMMNC vs. 13% in the placebo group (Relative risk [RR] 1.46; 95% confidence interval [CI] 0.62 to 3.42). The safety outcome (all-cause mortality, occurrence of malignancy or hospitalization due to infection) was not significantly different between the groups (RR 1.46; 95%CI 0.63 to 3.38), neither was all-cause mortality at six months with 5% vs. 6% (RR 0.78; 95%CI 0.22 to 2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups.
Conclusions—Repetitive intra-arterial infusion of autologous BMMNC into the common femoral artery did not reduce major amputation rate in patients with severe, non-revascularizable limb ischemia compared to placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC as well as the placebo group underlines the essential role for placebo-controlled design of future trials.
Clinical Trial Registration Information—ClinicalTrials.gov. Identifier: NCT00371371.
- Received August 22, 2014.
- Revision received December 31, 2014.
- Accepted January 5, 2015.