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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 120
- 试验地点
- 7
- 主要终点
- Change in Oxygenation Index (OI)
研究概览
简要总结
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).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Human Mesenchymal Stromal Cells
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.
干预措施: Human Mesenchymal Stromal Cells (Biological)
Cell Reconstitution Media
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.
干预措施: Cell Reconstitution Media (Biological)
结局指标
主要结局
Change in Oxygenation Index (OI)
时间窗: 36 hours
Change in OI from baseline over the 36 hours (6, 12, 18, 24, 30, 36 hours) following the initiation of the study product infusion. Lower values are considered better.
次要结局
- Acute Lung Injury Score (LIS)(7 days)
- Pulmonary Dead Space Fraction(7 days)
- Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score)(7 days)
- Ventilator Free-days (VFD) Over 14 Days(14 days)
- Occurrence of Thromboembolic Events(60 days)
- Ventilator Free-days (VFD) Over 28 Days.(28 days)
- Duration of Assisted Ventilation Over 28 Days(28 days)
- Percentage of Patients Achieving Pressure Support Ventilation for 2 Hours(28 days)
- Occurrence of Infection(14 days)
- Sequential Organ Failure Assessment (SOFA) Over 7 Days(7 days)
- Non-pulmonary Sequential Organ Failure Assessment (SOFA) Over 7 Days(7 days)
- All-cause Mortality(60 days)
- Glasgow Outcome Score (GCS)(60 days)
- Plasma Angiopoietin-2(72 hours)
- Plasma Receptor for Advanced Glycation Endproducts (RAGE)(72 hours)
- Plasma Interleukin-6 (IL-6)(72 hours)
- Plasma Interleukin-8 (IL-8)(72 hours)
- Plasma Tumor Necrosis Factor Receptor 1 (TNFR-1)(72 hours)
- Plasma Protein C(72 hours)
- Plasma Angiopoietin-1 (ANG-1)(72 hours)
- Plasma Lipoxin A4(72 hours)
- Plasma Resolvin D1(72 hours)
- Plasma Keratinocyte Growth Factor (KGF)(72 hours)
- Urine Microalbumin(48 hours)
- Total Protein in Min-bronchoalveolar Lavage (mBAL)(2 days)
- Tolerability of the hMSCs - Incidence of Pre-specified Infusion-associated Events and Unexpected Severe Adverse Events(24 hours)
研究者
Michael A. Matthay
Professor
University of California, San Francisco