A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit

Abstract

Background: Community-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP).

Methods: In addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20-30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20-30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union's Horizon 2020 Research and Innovation Program.

Discussion: SEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination.

Trial registration: NCT03158727 , retrospectively registered on 9 May 2017.

Keywords: Adjunctive therapy; Clinical trial; Community acquired bacterial pneumonia; Mesenchymal stem cells; Study protocol.

Fig. 1

Adipose-derived mesenchymal stem cells are sampled from human adipose tissue and expanded ex vivo. Their immunomodulatory and anti-microbial effects are utilised for the treatment of sCABP. eASC MoA: eASCs modulate inflammation through the generation of regulatory immune cells (e.g. Tregs, M2 Mph) by reducing pro-inflammatory cytokines (e.g. TNFα, IL-6, IL-8); increasing the release of the anti-inflammatory cytokine IL-10; inhibiting apoptosis of immune cells; and reducing lymphocyte, neutrophil and macrophage infiltration. eASCs also have anti-microbial effects as they release peptides with antimicrobial properties (e.g. LL-37) and increase the phagocytic capacity of monocytes, macrophages and neutrophils. Due to these properties, eASCs can reduce organ injury and increase functionality, thus conferring a therapeutic benefit [11]. eASC expanded adipose-derived mesenchymal stem cell, IFN interferon, IL interleukin, KGF keratinocyte growth factor, M2 Mph macrophages, MoA mode of action, sCABP severe community-acquired bacterial pneumonia, Treg regulatory T cell, TNFα tumour necrosis factor alpha

Fig. 2

Schedule of enrolment, interventions, and assessments

Fig. 3

a Study design for SEPCELL. A phase Ib/IIa, randomised, multicentre, double-blind, placebo-controlled study to assess the safety, tolerability and efficacy of eASCs (Cx611) administered intravenously, in addition to SoC therapy, to patients with sCABP. An amendment to the study protocol extended the follow-up period to 2 years (Table 2). b Trial flow diagram for SEPCELL. BL baseline, CABP community-acquired bacterial pneumonia, SPIRIT Standard Protocol Items: Recommendations for Interventional Trials, eASC expanded allogeneic adipose-derived mesenchymal stem cell, IV intravenous, SAE serious adverse event, sCABP severe community-acquired bacterial pneumonia, SoC standard of care. *From initiation of mechanical ventilation and/or vasopressors administration; **Screening procedures will start as soon as informed consent is signed