Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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This is a Phase 2b, randomized, double-blind, placebo-controlled, multi-center study to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS). This study is the extension of the Phase 1 pilot study (NCT01775774) and Phase 2a study (NCT02097641).

Detailed Description
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This clinical study design is a randomized, double-blinded, placebo-controlled Phase 2b clinical trial using a 10 million cell/kg dose of human Mesenchymal Stromal Cells (hMSCs). Subjects will be randomized in a 1:1 randomization scheme to receive hMSCs or cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) as the placebo; the study will enroll 120 patients who achieve a stable clinical baseline and receive study product (either hMSCs or the placebo). The Data and Safety Monitoring Board (DSMB) will review adverse outcomes and protocol compliance. A pre-specified interim review will occur after 60 subjects have been enrolled and received study product; enrollment will continue during the DSMB review. All pre-specified clinically important events and unexpected serious adverse events including death during hospitalization up to 60 days will be reported to the DSMB on an ongoing basis; the study will be stopped for a safety evaluation by the DSMB if they have any concerns or if three subjects have pre-specified clinically important events or unexpected serious adverse events except death since death will be common in this critically ill population due the nature of the underlying illness (e.g., ARDS).

Official Title
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A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) for the Treatment of Acute Respiratory Distress Syndrome

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Biological: Human Mesenchymal Stromal Cells
* Biological: Cell Reconstitution Media


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be eligible for inclusion if they meet all of the below criteria within 14 days of initial ICU admission. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment: Acute onset (defined below) of: A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio <250 mmHg and ≥5 cm H2O positive end-expiratory airway pressure (PEEP), as per the Berlin Criteria. Bilateral infiltrates consistent with pulmonary edema (defined below) on the frontal chest radiograph, or bilateral ground glass opacities on a chest CT scan. No clinical evidence of left atrial hypertension as a primary explanation for the bilateral pulmonary infiltrates. If the cause of ARDS is trauma, additional inclusion criteria will include ONE of the following relevant risk factors for developing ARDS: Hypotension (systolic blood pressure[SBP] < 90 mmHg) in the field or in the first 24 h after injury, or Transfusion of 3 units of blood products in the first 24 hours following injury, or Meets the new Critical Administration Threshold (CAT) criteria with at least 3 units of blood in one hour, or Blunt or penetrating torso trauma, or Long bone fractures, or The highest level of institutional trauma activation Exclusion Criteria: Age less than 18 years Greater than 72 hours since first meeting ARDS criteria per the Berlin definition of ARDS Greater than 14 days since initial ICU admission Inability to administer study product within 14 days of ICU admission PaO2/FiO2 ≥ 250 mmHg after consent obtained and before study product is administered Unable to obtain informed consent/no surrogate available Pregnant or lactating In custody of law enforcement officials Burns > 20% of total body surface area WHO Class III or IV pulmonary hypertension History of cancer treatment in the last 2 years except for non-melanotic skin cancers Underlying medical condition for which 6-month mortality is estimated to be > 50% Moribund patient not expected to survive 24 hours Advanced chronic liver disease (Child-Pugh Score > 12) Severe chronic respiratory disease with the use of home oxygen Severe traumatic brain injury - defined as: A patient who has undergone intracranial neurosurgical intervention for monitoring or therapy (intracranial pressure monitoring, external ventricular drain, craniotomy), or Intracranial injury by head CT (does not include patients with minimal subarachnoid injury and/or minor skull fracture), or Post-resuscitation Glasgow Coma Score (GCS) < 9 assessed after sedation interruption, or Non-survivable head injury as assessed by neurosurgery Evidence of anoxic brain injury History of stroke within the last 3 years No intent/unwillingness to follow lung protective ventilation strategy Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV) Anticipated extubation within 24 hours of enrollment Clinical evidence of left atrial hypertension as measured by a pulmonary arterial wedge pressure > 18mmHg or left ventricular failure measured by an echocardiogram with a left ventricular ejection fraction less than 40%. Clinical judgement will determine if either of these measurements needs to be carried out.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: For this Phase 2b trial, after informed consent is given, an assignment will be made by computer-generated randomization to administer either hMSCs therapy or placebo with a 1:1 allocation to the hMSCs:placebo arms.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Mesenchymal Stromal Cells<br>A single dose of 10 million cells/kg predicted body weight (PBW) Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells will administered intravenously over approximately 60-80 minutes. | Biological: Human Mesenchymal Stromal Cells<br>* Immediately prior to administration, the study product will be thawed and diluted 1:1 with reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40). Additional reconstitution media is added to a final product volume of 300 mL.<br>* Other names: hMSCs;|
| Experimental: Cell Reconstitution Media<br>A single dose of cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) will administered intravenously over approximately 60-80 minutes. | Biological: Cell Reconstitution Media<br>* 300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40)<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxygenation index (OI) | Change in OI from baseline over the 36 hours following the infusion of study product | 36 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Lung Injury Score (LIS) | LIS over 7 days, or on the last day of positive pressure ventilation prior to day 7. The LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used. | 7 days | 
| Pulmonary Dead Space Fraction | Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2 | 7 days | 
| Chest radiograph assessment of pulmonary edema (RALE score) | RALE score at day 1, 2, 3 and 7. To calculate RALE, each radiographic quadrant is scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants is summed. The RALE score ranges from 0 (best) to 48 (worst). | 7 days | 
| Ventilator free-days | Ventilator free-days over 7, 14 and 28 days | 28 days | 
| Duration of assisted ventilation over 28 days | Duration of assisted ventilation over 28 days in the survivors | 28 days | 
| Percentage of patients achieving pressure support ventilation for 2 hours | Percentage of patients achieving pressure support ventilation equal to 5 cm H2O with positive end-expiratory pressure (PEEP) equal to 5 cm H2O for 2 hours | 28 days | 
| Occurrence of Infection | Superficial incisional/wound infections, deep incisional wound infections, and organ/space infections, and ventilator associated pneumonia (all during the 14 days after enrollment) | 14 days | 
| Sequential Organ Failure Assessment (SOFA) over 7 days | SOFA score at 3 and 7 days. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst). | 7 days | 
| All-cause hospital mortality | All-cause hospital mortality at 14, 28 and 60 days | 60 days | 
| Glasgow Outcome Score (GCS) | Glasgow Outcome Score at hospital discharge. The GCS is a scale to evaluate level of consciousness in patients with acute brain injury. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst) | 60 days | 
| Percentage of patients occurred any thromboembolic events | Thromboembolic events are measured by ultrasound of the deep venous system or CT-angiography of the chest ordered for clinical purposes/by treating clinicians | 60 days | 
| Plasma angiopoietin-2 | Change in levels of plasma angiopoietin-2 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma Receptor for Advanced Glycation Endproducts (RAGE) | Change in levels of plasma RAGE from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma interleukin-6 | Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma interleukin-8 | Change in levels of plasma interleukin-8 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma Soluble tumor necrosis factor 1 (sTNF-1) | Change in levels of plasma sTNF-1 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma protein C | Change in levels of plasma protein C from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma lipoxin A4 | Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma Resolvin D1 | Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma angiopoietin-1 | Change in levels of plasma angiopoietin-1 from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Plasma keratinocyte growth factor (KGF) | Change in levels of plasma KGF from baseline compared to 6, 24, 48 and 72 hours | 72 hours | 
| Urine microalbumin | Change in levels of urine microalbumin from baseline compared to 24 and 48 hours | 48 hours | 
| Total protein in min-bronchoalveolar lavage (mBAL) | Change in total protein levels in from baseline to day 2 | 2 days | 
| Tolerability of the hMSCs - incidence of pre-specified infusion-associated events and unexpected severe adverse events | Tolerability of the hMSCs, defined as the incidence of pre-specified infusion-associated events and unexpected severe adverse events in ARDS patients treated with human MSCs | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome