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.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Keywords: Adipose-derived mesenchymal stromal cells; Advanced therapy medicinal products; Cell therapy; Critical limb ischemia; Diabetes mellitus; Phase II clinical trial; Randomized.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Flowchart: 90 patients will be recruited in the study and randomly allocated to three groups (high-dose group = 30; low-dose group = 30; control group = 30). The assessment will be done 24 h and 3, 6, and 12 months, respectively

Fig. 2

Cell therapy product flowchart. From GMP laboratory to the patient. MCB, master cell bank; WCB, working cell bank; MSC, mesenchymal stromal cells. Ad-MSC are isolated from the adipose tissue sample and cultured at two passages until reaching a minimum dose of 250 × 106 cells. Characterization of the cells and quality controls are established during the whole process. When a study subject is assigned to active treatment group, the sponsor notifies the assigned WCB laboratory to thaw and culture the cells in one passage. The batch is then packaged, labeled, and sent to the pharmacy service of the intended hospital. Manufacture process has been authorized by the Spanish competent authority (AEMPS), PEI number 15-103 Version 4:7/07/2019.

Fig. 3

MCB and WCB laboratories. Different laboratories have been assigned to the hospitals. MCB, master cell bank; WCB, working cell bank; NUC, Navarra University Hospital; SUH, Salamanca University Hospital; GMGUH, Gregorio Marañon General University Hospital; VAUCH, Virgen de la Arrixaca University Clinical Hospital; LFUH, La Fe University Hospital; VCUH, Valladolid Clinical University Hospital; LPUH, La Paz University Hospital; VE-CRH, Queen Victoria Eugenia-Cruz Roja Hospital; FJD, Jimenez Diaz Foundation University Hospital; HGUA, General University Hospital Alicante

Fig. 4

Once the targeted muscular injection points are selected (upper panel), repeated administrations of cell therapy are directly, easily, and minimally invasive administered into the lower part of the limb (lower panel)