Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial

Abstract

Purpose: Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS).

Methods: This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers.

Results: No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO₂/FiO₂ < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365.

Conclusions: Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.

Trial registration: ClinicalTrials.gov NCT02611609.

Keywords: Acute respiratory distress syndrome (ARDS); Multipotent adult progenitor cells (MAPC); Stem cells.

Fig. 1

Trial Design for Cohort 3

Fig. 2

Ratio of Day 7 to baseline values of biomarker plasma concentrations. The ratio of the biomarker value at Day 7 compared to the baseline values are presented as medians with upper and lower quartiles. Biomarkers include: angiopoietin 1 (ANG1), angiopoietin 2 (ANG2), C-X-C Motif chemokine ligand 10 (CXCL10), Interferon (IFN) gamma, interleukin 1 beta (IL-1b), interleukin 1 receptor 2 (IL-1R2), interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 12 (IL-12), keratinocyte growth factor (KGF), matrix metalloproteinase 2 (MMP-2), programmed cell death protein (PD-1), receptor for advanced glycation end-products (RAGE), regulated on activation, normal T cell expressed and secreted (RANTES), surfactant protein D (SP-D), tumour necrosis factor alpha (TNF alpha), soluble TNF receptor 1 (sTNFR1) and thrombospondin 1 (TSP-1). Green = patients receiving multipotent adult progenitor cells (n = 19); Blue = patients receiving placebo (n = 7)