Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock: A Multi-Center, Double Blind, Phase II Randomized Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 296
- 试验地点
- 2
- 主要终点
- Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy
研究概览
简要总结
Septic shock is associated with substantial burden in terms of both mortality and morbidity for survivors of this illness. Pre-clinical sepsis studies suggest that mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance pathogen clearance and tissue repair and reduce death. Our team has completed a Phase I dose escalation and safety clinical trial that evaluated MSCs in patients with septic shock. The Cellular Immunotherapy for Septic Shock Phase I (CISS) trial established that MSCs appear safe and that a randomized controlled trial (RCT) is feasible. Based on these data, the investigators have planned a phase II RCT (UC-CISS II) at several Canadian academic centres which will evaluate intermediate measures of clinical efficacy (primary outcome), as well as biomarkers, safety, clinical outcome measures, and a health economic analysis (secondary outcomes).
详细描述
Septic shock is a devastating illness and the most severe form of infection seen in the intensive care unit (ICU). It is characterized by cardiovascular collapse, failure of organs and is common with severe repercussions including a mortality of 20-40%. Survivors suffer long-term impairment in function and reduced quality of life (QOL). Despite decades of research examining different immune therapies, none has proven successful and supportive care remains the mainstay of therapy, at a cost of approximately 4-billion dollars in Canada annually. MSCs represent a potentially novel treatment for sepsis because in animal models, MSCs have been shown to modulate the immune system, increase pathogen clearance, restore organ function, and reduce death.
The Phase II multi-centre double blind Umbilical Cord Cellular Immunotherapy for Septic Shock RCT (UC-CISS II) will examine intermediate measures of clinical efficacy (primary outcome) as well as biomarkers, safety, clinical outcome measures, and a health economic analysis (secondary outcomes). To answer these aims, UC-CISS II will randomize 296 patients who are admitted to the ICU with septic shock to 300 million cryopreserved, allogeneic, umbilical cord-derived MSCs or placebo across several Canadian academic centres over approximately 2.5 years.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-Blind
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
- •A participant must meet all the following inclusion criteria at time of randomization to be eligible:
- •At least 18 years of age AND
- •Requirement for admission to the intensive care unit AND
- •Index admission to the intensive care unit AND
- •Cardiovascular organ failure for at least 1 consecutive hour defined by the requirement of at least 5 mcg/min of norepinephrine or 100 mcg/min of phenylephrine or 0.03 U/min vasopressin AND
- •Clinician impression that cardiovascular organ failure is related to infection AND
- •There is at least 1 other acute organ failure according to modified individual Sequential Organ Failure Assessment Scores within 24 hours of meeting Cardiovascular organ failure defined by:
- •Respiratory failure: invasive or non-invasive mechanical ventilation with a positive end expiratory pressure (PEEP) >/= 5 cm H2O and a partial pressure of oxygen/fractional inspired oxygen concentration (P/F ratio </= 200), OR high-flow nasal canula oxygen therapy (minimum total flow rate of 30 lpm and 40% FiO2); OR
- •Hematological failure: platelet count of </= 100 X 10^9/L OR
- •Acute kidney injury: acute renal insufficiency with a creatinine of >/= 200 umol/L, or the requirement for new renal replacement therapy, or for participants with known chronic renal failure but not on dialysis, a 50% increase in their baseline creatinine concentration OR
- •Organ hypoperfusion: a lactate >/= 4 mmol/L
- •Acute organ failures that meet eligibility criteria must not have been present for greater than 48 hours prior to meeting the eligibility criteria.
排除标准
- •Patients will be excluded if they have at least one of the following at time of randomization:
- •Another form of shock (cardiogenic, hypovolemic, obstructive) OR
- •History of known chronic pulmonary hypertension with a WHO functional class of IV OR
- •History of severe chronic pulmonary disease requiring home oxygen OR
- •History of severe chronic cardiac disease including congestive heart failure or valvular dysfunction with a New York Heart Association Functional class IV or severe chronic ischemic heart disease with a Canadian Cardiovascular Society angina class score IV OR
- •History of severe chronic liver disease (Child-Pugh Class C or model for end stage liver disease (MELD) Score >= 15) OR
- •Malignancy in previous 1 year (excluding resolved non-melanoma skin cancer) OR
- •Treating physician impression that death is imminent within the 12 hours after meeting eligibility criteria OR
- •Pregnant or lactating OR
- •Family or patient not committed to aggressive care
研究组 & 干预措施
Placebo
Intravenous infusion of placebo, with excipients
干预措施: Placebo (Other)
Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs)
Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells
干预措施: Allogeneic umbilical cord-derived human mesenchymal stromal cells (Biological)
结局指标
主要结局
Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy
时间窗: Through to 28 days post-randomization
The number of days free from each of these support measures
次要结局
- Biomarkers - Vascular permeability(At baseline, 1, 3 and 7 days post-randomization)
- Biomarkers - Muscle weakness(At baseline, 1, 3 and 7 days post-randomization)
- Health Economic Analysis(Through to 28 days post-randomization)
- Biomarkers - Pathogen clearance(At baseline, 1, 3 and 7 days post-randomization)
- Biomarkers - Inflammatory mediators and cytokines(At baseline, 1, 3 and 7 days post-randomization)
- Safety - Expected Adverse Events(Through to 28 days post-randomization)
- Length of ICU Stay (in days)(Number of elapsed days from admission until ICU discharge, up to 1 year)
- Days free from renal replacement therapy(Through to 90 days post-randomization)
- Patient Reported Outcomes - Functional Independence Measure (FIM)(At 30 days, 6 months and 1 year post-randomization)
- Biomarkers - Acute kidney injury(At baseline, 1, 3 and 7 days post-randomization)
- Safety - Adverse Event(Through to 7 days post-randomization)
- Safety - Serious and Unexpected Adverse Events(Through to 28 days post-randomization)
- Mortality(In ICU (through study completion, up to 1 year), in hospital (through study completion, up to 1 year), 28 days, 90 days, 6 months and 1 year post-randomization)
- ICU Re-Admissions(During index study hospital admission (through study completion, up to 1 year))
- Organ Failure Rates(Through to 90 days post-randomization)
- Days free from vasopressors(Through to 90 days post-randomization)
- Hospital Re-Admissions(At 28 days, 90 days and 1 year post-randomization)
- Days free from mechanical ventilation(Through to 90 days post-randomization)
- Length of Hospital Stay (in days)(Number of elapsed days from admission until hospital discharge, up to 1 year)
- Patient Reported Outcomes - Short Form Survey-36 (SF-36)(At 30 days, 6 months and 1 year post-randomization)