Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial)

Abstract

Background Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. Methods A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. Discussion Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. Trial registration ClinicalTrials.govNCT04466007. Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Mesenchymal Stromal Cells Combined With Elastin-Like Recombinamers Increase Angiogenesis In Vivo After Hindlimb Ischemia

“…These attributes, together with their immunomodulatory properties and their regenerative capacity, make them excellent potential candidates for the treatment of hindlimb ischemia. MSCs have been tested in several preclinical studies ( Iwase et al, 2005 ; Al-Khaldi et al, 2003 ; Kinnaird et al, 2004 ), and although the majority of the reported clinical trials used autologous MNC, there are also some studies where MSCs have been and are currently being assessed for this purpose in patients, either delivered locally through the intramuscular route or systemically, with promising results ( Soria-Juan et al, 2019 ; Soria-Juan et al, 2021 ; Gupta et al, 2013 ). MSC effects may depend more on secreted soluble factors than on engraftment and transdifferentiation.…”

Cellular therapies in no-option critical limb ischemia: present status and future directions

“…A randomized, placebo-controlled, multi-center study with single-dose intramuscular administration of ASCs from healthy donors in diabetic N-O CLI patients is ongoing [ 40 ].…”

Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia

“…Classification methods for CLI severity were devised to estimate amputation probability and treatment outcomes. Historically, the Fontaine and Rutherford classification systems categorized patients based on clinical criteria alone or in conjunction with objective hemodynamic evidence [ 72 ].…”

“…For instance, Benoit et al accomplished a meta-analysis that exhibited increased ABI values in 63.2% of patients, significantly increased TcPO2 in 76.9% of patients, pain relief in nearly 90%, and claudication interval extension in 89.5% of patients [ 3 ]. Angiography is a kind of functional endpoint that utilizes mean percentage vascular flow change from angiographic techniques, including duplex ultrasonography (DUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA), to evaluate the target limb's vascularity [ 72 ].…”

“…In this regard, Soria B et al designed the NOMA Trial to evaluate the safety, tolerability, and efficacy of the intramuscular administration of allogeneic AD-MSCs in 90 eligible patients with type 2 diabetes with critical lower limb ischemia and no possibility of revascularization in 3 parallel groups (placebos, low-dose AD-MSCs, and high-dose AD-MSCs) [ 72 ]. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) …”