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)

Bárbara Soria-Juan ,Luis Riera Del Moral,César Aparicio,José Manuel Ligero,Lucía Llanos Jiménez,Manuel Miralles,Mariano García‐Arranz ,Juan R Tejedo ,Enrique J Andreu,Luis Hernández‐Blasco ,Abdelkrim Hmadcha,Francisco J Bedoya,Ana M García-Hernández ,María Eugenia Fernández‐Santos ,Miriam López Parra ,Fermín Sánchez‐Guijo ,Eva Villarón ,Lukasz Grochowicz,Francisco Morant,Damián Garcı́a-Olmo ,Antonio De La Cuesta Diaz,Rosa María Pérez Yáñez ,Franz Martı́n ,Pedro Marı́n ,Etelvina Andreu,Alejandro González ,José Marı́a Moraleda ,Francisco Lozano ,Ignacio Mahíllo‐Fernández ,Gregorio Castellanos,Lourdes Del Rio Sola,Bernat Soria

doi:10.1186/s13063-021-05430-2

Abstract

BackgroundChronic 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.MethodsA 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.DiscussionChronic 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 registrationClinicalTrials.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.

Highlights

Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus
The study that we propose here focuses on the development and optimization of an advanced therapy medicinal product (ATMP) based on adipose tissue-derived mesenchymal stromal cells (MSC) (Ad-MSC) to be administered intramuscularly to patients with type 2 DM and Critical lower limb ischemia (CLI) within a multicenter randomized phase II clinical trial, favoring the translation of this cellular therapy to clinical practice
Efficacy of the intramuscular administration of autologous Ad-MSC in type 2 DM patients with CLI was demonstrated in the pilot study conducted by Riera et al, showing a statistically significant improvement in health-related quality of life, an increase in Ankle-brachial index (ABI), and a decrease in RB category in the posttreatment period [32]

Summary

Introduction

Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. 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. Efforts to prevent loss of the affected limb include soft tissue debridement, minor amputations, and even skin grafts, all of which are costly procedures In this context, given the high number of amputations that are still practiced annually worldwide, we are still in need of a cost-effective and easy-to-apply treatment [7]. In a phase I/II, open-label, non-comparative clinical trial, safety and feasibility of treatment with autologous mesenchymal stromal cells (MSC) derived from BM and administered intra-arterially in patients with type 2 DM and lower limb ischemia was studied. If proven safe and effective, an accessible, easy and minimally invasive treatment will be available for patients without any other option or that can even be associated with existing surgical treatments and improve their results

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