Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial

Abstract

Background: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.

Methods: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H₂O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 10⁶/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.

Findings: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H₂O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.

Interpretation: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.

Funding: National Heart, Lung, and Blood Institute.

Figure 1:. Trial profile

DVT=deep-vein thrombosis. MSC=mesenchymal stromal cell. PaO₂:FiO₂=ratio of partial pressure of oxygen to fractional inspired oxygen. *Numbers total more than 975 because some patients met multiple exclusion criteria. †Do not resuscitate or limit on life support order in place.

Figure 2:. Mortality to day 28 and day 60 for mesenchymal stromal cell therapy versus placebo

APACHE III=Acute Physiology and Chronic Health Evaluation III score; HR=hazard ratio.

Figure 3:. Changes in angiopoietin 2 concentrations in plasma from baseline to 6 and 24 h

Data are mean (SE) after log transformation. MSC=mesenchymal stromal cell. *p=0·005 compared with placebo.

Figure 4:. MSC viability measured after simple thawing and dilution versus after cell wash and reconstitution

Data are mean (SD) based on viability measurements at 0, 30, 60, 120, and 180 min after removal from cryopreservation. MSC=mesenchymal stromal cell. *p=0·004 compared with before cryopreservation.