Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START)

A Phase 1 Multi-center Clinical Trial of Allogeneic Bone Marrow-derived Human Mesenchymal Stem Cells for the Treatment of Acute Respiratory Distress Syndrome

This is a Phase 1, open label, dose escalation, multi-center clinical trial of Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) for the treatment of Acute Respiratory Distress Syndrome (ARDS). The purpose of this study is to assess the safety of hMSCs in patients with ARDS.

Study Overview

• Status: Completed
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells

Detailed Description

The primary objective of this study is to assess the safety of intravenous infusion of Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells (hMSCs) in patients with ARDS.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients will be eligible for inclusion if they meet all of the below criteria. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment:

Acute onset (defined below) of:

1. A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio < 200 with at least 8 cm H2O positive end-expiratory airway pressure (PEEP)
2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
3. No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.

In addition to meeting inclusion criteria, enrollment must occur within 96-hours of first meeting ARDS criteria per the Berlin definition of ARDS.

Exclusion Criteria:

1. Age less than 18 years
2. Greater than 96 hours since first meeting ARDS criteria per the Berlin definition of ARDS
3. Pregnant or breast-feeding
4. Prisoner
5. Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last 2 years
6. Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
7. Moderate to severe liver failure (Childs-Pugh Score > 12)
8. Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen
9. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest).
10. Major trauma in the prior 5 days
11. Lung transplant patient
12. No consent/inability to obtain consent
13. Moribund patient not expected to survive 24 hours
14. WHO Class III or IV pulmonary hypertension
15. Documented deep venous thrombosis or pulmonary embolism within past 3 months
16. No arterial line/no intent to place an arterial line
17. No intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol
18. Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells; A dose-escalation with 3 cohorts with 3 subjects/cohort who receive doses of 1, 5 and 10 million cells/kg predicted body weight (PBW). Proceed from lower dose to next higher dose if no safety concerns for each cohort.	Biological: Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells; Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Pre-specified Infusion Associated Adverse Events	Any of the following occurring within 6 h of mesenchymal stem-cell infusion: Addition of a third vasopressor or an increase in vasopressor dose greater than or equal to the following:; Norepinephrine: 10 μg per min; Phenylephrine: 100 μg per min; Dopamine: 10 μg/kg per min; Epinephrine: 0·1 μg/kg per min; Hypoxaemia requiring an increase in the fraction of inspired oxygen of ≥0·2 and increase in positive end-expiratory airway pressure level of 5 cm H2O or more to maintain transcutaneous oxygen saturations in the target range of 88-95%; New cardiac arrhythmia requiring cardioversion; New ventricular tachycardia, ventricular fi brillation, or asystole; A clinical scenario consistent with transfusion incompatibility or transfusion-related infection; Cardiac arrest or death within 24 h of mesenchymal stem-cell infusion	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Severe Adverse Events (SAEs)	The number of participants with a severe adverse event during the study was assessed.	Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first.
Ventilator Free Days at Study Day 28	Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given.	time of initiating unassisted breathing to day 28
Duration of Vasopressor Use (Days)	Days on vasopressor to day 28 after study enrollment	28 days
ICU Free Days to Day 28		28 days after study enrollment
Hospital Survival to Day 60	The number of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.	60 days after randomization
Mortality at Hospital Discharge	The number of patients expired at hospital discharge.	From study enrollment to Hospital discharge

Collaborators and Investigators

• Sponsor: Michael A. Matthay
• Collaborators: Massachusetts General Hospital; National Heart, Lung, and Blood Institute (NHLBI); University of Pittsburgh; Stanford University; University of Minnesota

Publications and helpful links

General Publications

• Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, Cosgrove K, Vojnik R, Calfee CS, Lee JW, Rogers AJ, Levitt J, Wiener-Kronish J, Bajwa EK, Leavitt A, McKenna D, Thompson BT, Matthay MA. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015 Jan;3(1):24-32. doi: 10.1016/S2213-2600(14)70291-7. Epub 2014 Dec 17.
• Liu KD, Wilson JG, Zhuo H, Caballero L, McMillan ML, Fang X, Cosgrove K, Calfee CS, Lee JW, Kangelaris KN, Gotts JE, Rogers AJ, Levitt JE, Wiener-Kronish JP, Delucchi KL, Leavitt AD, McKenna DH, Thompson BT, Matthay MA. 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. Ann Intensive Care. 2014 Jul 3;4:22. doi: 10.1186/s13613-014-0022-z. eCollection 2014.
• Asmussen S, Ito H, Traber DL, Lee JW, Cox RA, Hawkins HK, McAuley DF, McKenna DH, Traber LD, Zhuo H, Wilson J, Herndon DN, Prough DS, Liu KD, Matthay MA, Enkhbaatar P. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014 Sep;69(9):819-25. doi: 10.1136/thoraxjnl-2013-204980. Epub 2014 Jun 2.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: January 18, 2013
• First Submitted That Met QC Criteria: January 24, 2013
• First Posted (Estimate): January 25, 2013

Study Record Updates

• Last Update Posted (Actual): August 14, 2017
• Last Update Submitted That Met QC Criteria: May 2, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Acute Respiratory Distress Syndrome; Acute Lung Injury; Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: ARDS MSC 001; 1U01HL108713-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No