Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome

Kathleen D. Liu, Jennifer G. Wilson, Hanjing Zhuo, Lizette Caballero, Melanie L. McMillan, Xiaohui Fang, Katherine Cosgrove, Carolyn S. Calfee, Jae Woo Lee, Kirsten N. Kangelaris, Jeffrey E. Gotts, Angela J. Rogers, Joseph E. Levitt, Jeanine P. Wiener-Kronish, Kevin L. Delucchi, Andrew D. Leavitt, David H. McKenna, B. Taylor Thompson, Michael A. Matthay

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Background: Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS. Methods: This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio). Results: This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU. Conclusions: Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses. Trial registration: Clinical Trials Registration: NCT01775774 and NCT02097641.

Original languageEnglish (US)
Article number22
Pages (from-to)1-9
Number of pages9
JournalAnnals of Intensive Care
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2014

Bibliographical note

Funding Information:
We want to thank the UCSF Clinical and Translational Research Institute for funding support and for early discussions that shaped this clinical trial design, and in particular Drs. June Lee and Ruben Rathnasingham as well as the National Heart, Lung and Blood Institute for funding support. We thank Drs. Elizabeth Leininger, Danny McAuley and Eric Seeley for helpful discussions relevant to the IND preparation and protocol design. We thank study coordinators and bone marrow transplant staff at all of the participating sites who have made the study possible. We appreciate the support of the NHLBI U01 HL10871301 grant plus the UCSF T1 Catalyst Program.

Funding Information:
Phase 2 is a randomized, double-blind placebo-controlled study using the maximally tolerated dose (MTD) of cells from the phase 1 study (up to 10 × 10 cell/kg predicted body weight). The MTD is the highest dose that is associated with no pre-specified infusion associated events or unexpected severe adverse attributed to the study product. Subjects will be randomized in a 2:1 randomization scheme to receive human MSCs or Plasma-lyte A placebo; the study will enroll 60 patients who achieve a stable clinical baseline and receive the investigational product. The coordinating center for the trial is at the University of California, San Francisco. Eligible study subjects will be enrolled in the phase 1 trial at the University of California, San Francisco, Stanford University, and the Massachusetts General Hospital. Planned phase 2 sites also include the University of Pittsburgh and the University of Vermont. The trial is funded by the National Institutes of Health through a Clinical and Translational Science Institute award to the University of California, San Francisco and through the National Heart, Lung and Blood Institute (NHLBI) Pilot Trials in Lung Disease U01 mechanism and the NHLBI-supported Production Assistance for Cellular Therapies (PACT) program at the University of Minnesota. The human MSCs are prepared from donor bone marrow at the University of Minnesota and shipped frozen to the clinical sites. Prior to administration, cells are thawed, washed and reconstituted at the clinical site, as detailed below. 6

Publisher Copyright:
© 2014, Liu et al.; licensee Springer.

Keywords

  • Acute lung injury
  • Clinical trial
  • Mesenchymal stem/stromal cell
  • Pulmonary edema

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