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

Michael A Matthay; Carolyn S Calfee; Hanjing Zhuo; B Taylor Thompson; Jennifer G Wilson; Joseph E Levitt; Angela J Rogers; Jeffrey E Gotts; Jeanine P Wiener-Kronish; Ednan K Bajwa; Michael P Donahoe; Bryan J McVerry; Luis A Ortiz; Matthew Exline; John W Christman; Jason Abbott; Kevin L Delucchi; Lizette Caballero; Melanie McMillan; David H McKenna; Kathleen D Liu

doi:10.1016/S2213-2600(18)30418-1

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

Lancet Respir Med. 2019 Feb;7(2):154-162. doi: 10.1016/S2213-2600(18)30418-1. Epub 2018 Nov 16.

Authors

Michael A Matthay¹, Carolyn S Calfee², Hanjing Zhuo³, B Taylor Thompson⁴, Jennifer G Wilson⁵, Joseph E Levitt⁶, Angela J Rogers⁶, Jeffrey E Gotts⁷, Jeanine P Wiener-Kronish⁸, Ednan K Bajwa⁴, Michael P Donahoe⁹, Bryan J McVerry⁹, Luis A Ortiz¹⁰, Matthew Exline¹¹, John W Christman¹¹, Jason Abbott³, Kevin L Delucchi¹², Lizette Caballero¹³, Melanie McMillan¹³, David H McKenna¹⁴, Kathleen D Liu²

Affiliations

¹ Department of Medicine and Anesthesia, University of California, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, CA, USA. Electronic address: michael.matthay@ucsf.edu.
² Department of Medicine and Anesthesia, University of California, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
³ Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
⁴ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Emergency Medicine, Stanford University, Stanford, CA, USA.
⁶ Department of Medicine, Stanford University, Stanford, CA, USA.
⁷ Department of Medicine and Anesthesia, University of California, San Francisco, CA, USA.
⁸ Department of Anesthesiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ Department of Medicine, Ohio State University Medical Center, Columbus, OH, USA.
¹² Department of Psychiatry, University of California, San Francisco, CA, USA.
¹³ Bone and Marrow Transplant Laboratory, University of California, San Francisco, CA, USA.
¹⁴ University of Minnesota, Molecular and Cellular Therapeutics, Saint Paul, MN, USA.

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.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Academic Medical Centers
Adult
Aged
Disease-Free Survival
Double-Blind Method
Female
Hospital Mortality*
Humans
Male
Mesenchymal Stem Cell Transplantation / methods*
Mesenchymal Stem Cell Transplantation / mortality
Middle Aged
Multivariate Analysis
Patient Safety*
Proportional Hazards Models
Prospective Studies
Respiratory Distress Syndrome / diagnosis
Respiratory Distress Syndrome / mortality*
Respiratory Distress Syndrome / therapy*
Risk Assessment
Severity of Illness Index
Statistics, Nonparametric
Survival Analysis
Treatment Outcome
United States

Associated data

ClinicalTrials.gov/NCT02097641

Abstract

Publication types

MeSH terms

Associated data

Grants and funding