Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock: A Multi-Center, Double Blind, Phase II Randomized Controlled Trial

Conditions
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Septic Shock, Sepsis, Pathologic Processes, Shock, Systemic Inflammatory Response Syndrome, Inflammation, Infections

Intervention / Treatment
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* Biological: Allogeneic umbilical cord-derived human mesenchymal stromal cells
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A participant must meet all the following inclusion criteria 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, OR high-flow nasal canula oxygen therapy (minimum total flow rate of 40 lpm); and a partial pressure of oxygen/fractional inspired oxygen concentration (P/F ratio) </= 200 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 admission to the ICU. Exclusion Criteria: Patients will be excluded if they have at least one of the following: 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

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: Randomized Controlled Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs)<br>Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells | Biological: Allogeneic umbilical cord-derived human mesenchymal stromal cells<br>* Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells<br>|
| Placebo Comparator: Placebo<br>Intravenous infusion of placebo, with excipients | Other: Placebo<br>* Intravenous infusion of placebo, with excipients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy | The number of days free from each of these support measures | Through to 28 days post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers - Vascular permeability | Markers of vascular permeability (ex: Angpt1 and 2) | At baseline, 1, 3 and 7 days post-randomization | 
| Biomarkers - Acute kidney injury | Markers of acute kidney injury (ex: Urine TIMP2-IGFBP7, IL-18) | At baseline, 1, 3 and 7 days post-randomization | 
| Biomarkers - Muscle weakness | Markers of muscle weakness (ex: micro RNA [miR] miR-181a, growth differentiation Factor-15) | At baseline, 1, 3 and 7 days post-randomization | 
| Biomarkers - Pathogen clearance | Mechanisms related to pathogen clearance (ex: cathelicidin, LL-37) | At baseline, 1, 3 and 7 days post-randomization | 
| Biomarkers - Inflammatory mediators and cytokines | Pro- and anti-inflammatory mediators and cytokines (ex: CRP, IL-6, IL-8, IL-10, IL-1B and IL1-RA) | At baseline, 1, 3 and 7 days post-randomization | 
| Safety - Adverse Event | Safety of study treatment administration, examined for the occurrence of any adverse event (which requires treatment or intervention) regardless of relationship to study treatment | Through to 7 days post-randomization | 
| Safety - Serious and Unexpected Adverse Events | Safety of study treatment administration, examined for the occurrence of serious and unexpected adverse events that are considered possibly or related to the study treatment | Through to 28 days post-randomization | 
| Safety - Expected Adverse Events | Safety of study treatment administration, examined for the occurrence of expected adverse events (including nosocomial infections, acute coronary syndrome, tachy and bradyarrhythmia, clinically important bleeding, ARDS and thrombotic/thromboembolic events) | Through to 28 days post-randomization | 
| Mortality | All-cause 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 | 
| Length of ICU Stay (in days) | Time in ICU | Number of elapsed days from admission until ICU discharge, up to 1 year | 
| Length of Hospital Stay (in days) | Time in hospital | Number of elapsed days from admission until hospital discharge, up to 1 year | 
| Hospital Re-Admissions | Re-admission to any hospital | At 28 days, 90 days and 1 year post-randomization | 
| ICU Re-Admissions | Re-admission to ICU during study hospital admission | During index study hospital admission (through study completion, up to 1 year) | 
| Organ Failure Rates | Organ failure rates (using Sequential Organ Failure Assessment Score), described individually and in composite | Through to 90 days post-randomization | 
| Days free from mechanical ventilation | Number of days free from mechanical ventilation | Through to 90 days post-randomization | 
| Days free from vasopressors | Number of days free from vasopressor agents | Through to 90 days post-randomization | 
| Days free from renal replacement therapy | Number of days free from renal replacement therapy | Through to 90 days post-randomization | 
| Patient Reported Outcomes - Functional Independence Measure (FIM) | FIM scores ranging from 18 to 126 (where the higher the score, the more independent the patient is) | At 30 days, 6 months and 1 year post-randomization | 
| Patient Reported Outcomes - Short Form Survey-36 (SF-36) | SF-36 scores ranging from 0 to 100 (with higher scores indicating better health status) | At 30 days, 6 months and 1 year post-randomization | 
| Health Economic Analysis | A cost-utility analysis of MSCs compared to placebo from a perspective of Canada's publicly funded health care system will be conducted | Through to 28 days post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal Stem Cells, Mesenchymal Stromal Cells, Randomized Controlled Trial, Cryopreserved, Allogeneic, Umbilical Cord, Phase II, Sepsis, Septic Shock