Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in patients with critical limb ischemia and type 2 diabetes with no possibility of revascularization: Study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).
Authors: Soria-Juan Barbara , Garcia-Arranz Mariano , Llanos Lucía , Aparicio César , Gonzalez Alejandro , Fernandez Ignacio Mahillo , Moral Luis Riera del , Grochowicz Lukasz , Andreu Enrique J. , Marin Pedro , Castellanos Gregorio , Moraleda Jose Maria , García-Hernández Ana María , Lozano Francisco S , Sanchez-Guijo Fermin , Villarón Eva María , Parra Miriam Lopez , Yañez Rosa María , Diaz Antonio De la Cuesta , Tejedo Juan Rigoberto , Bedoya Francisco J , Martin Franz , Miralles Manuel , Sola Lourdes del Rio , Fernández-Santos María Eugenia , Ligero José Manuel , Morant Francisco , Hernández-Blasco Luis , Andreu Etelvina , Hmadcha Abdelkrim , Garcia-Olmo Damian , Soria Bernat 
Published: March 2021

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. 90 eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: the 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.gov NCT04466007. Registered on January 07, 2020.