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)
Authors: Soria-Juan Barbara , Garcia-Arranz Mariano , Llanos Jiménez Lucía , Aparicio César , Gonzalez Alejandro , Mahillo Fernandez Ignacio , Riera del Moral Luis , Grochowicz Lukasz , Andreu Enrique J. , Marin Pedro , Castellanos Gregorio , Moraleda Jose Maria , García-Hernández Ana Maria , Lozano Francisco S. , Sanchez-Guijo Fermin , Villarón Eva María , Parra Miriam Lopez , Yañez Rosa María , de la Cuesta Diaz Antonio , Tejedo Juan Rigoberto , Bedoya Francisco J. , Martin Franz , Miralles Manuel , del Rio Sola Lourdes , Fernández-Santos María Eugenia , Ligero José Manuel , Morant Francisco , Hernández-Blasco Luis , Andreu Etelvina , Hmadcha Abdelkrim , Garcia-Olmo Damian , Soria Bernat 
Published: September 2021

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.