Acute Respiratory Distress Syndrome
Conditions
Keywords
Acute Respiratory Distress Syndrome, Acute Lung Injury, Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells
Brief summary
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.
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.
Interventions
Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Stanford University
University of Pittsburgh
University of Minnesota
Michael A. Matthay
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Pre-specified Infusion Associated Adverse Events | 24 hours | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator Free Days at Study Day 28 | time of initiating unassisted breathing to 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. |
| Duration of Vasopressor Use (Days) | 28 days | Days on vasopressor to day 28 after study enrollment |
| Incidence of Severe Adverse Events (SAEs) | Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first. | The number of participants with a severe adverse event during the study was assessed. |
| Hospital Survival to Day 60 | 60 days after randomization | The number of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60. |
| Mortality at Hospital Discharge | From study enrollment to Hospital discharge | The number of patients expired at hospital discharge. |
| ICU Free Days to Day 28 | 28 days after study enrollment | — |
Countries
United States
Participant flow
Recruitment details
This dose-escalation Phase 1 clinical trial with 3 cohorts with 3 subjects/cohort was performed in 7 centers in USA between July 2013 to January 2014.
Participants by arm
| Arm | Count |
|---|---|
| Human Mesenchymal Stem Cells 1 Million Cells/kg PBW Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts. | 3 |
| Mesenchymal Stem Cells 5 Million Cells/kg PBW Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts. | 3 |
| Mesenchymal Stem Cells 10 Million Cells/kg PBW Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells were administered intravenously into the 3 planned dosing cohorts. | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Human Mesenchymal Stem Cells 1 Million Cells/kg PBW | Mesenchymal Stem Cells 5 Million Cells/kg PBW | Mesenchymal Stem Cells 10 Million Cells/kg PBW | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Age, Continuous | 58.0 years | 58.3 years | 48.3 years | 54.9 years |
| APACHE III Score | 91.7 scores on a scale | 89.7 scores on a scale | 88.3 scores on a scale | 89.9 scores on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Primary cause of ARDS Aspiration | 1 participants | 2 participants | 0 participants | 3 participants |
| Primary cause of ARDS Pneumonia | 1 participants | 1 participants | 2 participants | 4 participants |
| Primary cause of ARDS Pre-eclampsia | 1 participants | 0 participants | 0 participants | 1 participants |
| Primary cause of ARDS Sepsis | 0 participants | 0 participants | 1 participants | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 9 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 1 / 3 | 1 / 3 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 0 / 3 |
Outcome results
Primary
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
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Incidence of Pre-specified Infusion Associated Adverse Events | 0 participants |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Incidence of Pre-specified Infusion Associated Adverse Events | 0 participants |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Incidence of Pre-specified Infusion Associated Adverse Events | 0 participants |
Secondary
Duration of Vasopressor Use (Days)
Days on vasopressor to day 28 after study enrollment
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Duration of Vasopressor Use (Days) | 4 day |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Duration of Vasopressor Use (Days) | 2 day |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Duration of Vasopressor Use (Days) | 0 day |
Secondary
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.
Time frame: 60 days after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Hospital Survival to Day 60 | 2 participants |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Hospital Survival to Day 60 | 2 participants |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Hospital Survival to Day 60 | 3 participants |
Secondary
ICU Free Days to Day 28
Time frame: 28 days after study enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | ICU Free Days to Day 28 | 14 day |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | ICU Free Days to Day 28 | 21 day |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | ICU Free Days to Day 28 | 18 day |
Secondary
Incidence of Severe Adverse Events (SAEs)
The number of participants with a severe adverse event during the study was assessed.
Time frame: Investigators conducted daily assessments for the presence of adverse events (AE) from enrollment through study day 28 or hospital discharge, whichever occurred first.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Incidence of Severe Adverse Events (SAEs) | 2 participants |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Incidence of Severe Adverse Events (SAEs) | 1 participants |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Incidence of Severe Adverse Events (SAEs) | 0 participants |
Secondary
Mortality at Hospital Discharge
The number of patients expired at hospital discharge.
Time frame: From study enrollment to Hospital discharge
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Mortality at Hospital Discharge | 1 participants |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Mortality at Hospital Discharge | 1 participants |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Mortality at Hospital Discharge | 0 participants |
Secondary
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 frame: time of initiating unassisted breathing to day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Human Mesenchymal Stem Cells: 1 Million Cellls/kg PBW | Ventilator Free Days at Study Day 28 | 18 day |
| Human Mesenchymal Stem Cells: 5 Million Cellls/kg PBW | Ventilator Free Days at Study Day 28 | 22 day |
| Human Mesenchymal Stem Cells: 10 Million Cellls/kg PBW | Ventilator Free Days at Study Day 28 | 20 day |