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 may 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 mesenchymal stem cells (MSCs) in patients with septic shock. The Cellular Immunotherapy for Septic Shock (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 (CISS2) at several Canadian academic centres which will evaluate safety, signals for clinical efficacy, and continue to examine potential mechanisms of action and biological effects of MSCs in septic shock.
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 Cellular Immunotherapy for Septic Shock RCT (CISS2) will continue to evaluate safety, assess if there are signals for clinical efficacy and determine mechanisms of action and biological effects of MSCs in septic shock. To answer these aims, CISS2 will randomize 114 patients who are admitted to the ICU with septic shock to 300 million cryopreserved, allogeneic, bone marrow derived MSCs or placebo across 10 Canadian centres over approximately 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
114
Cryopreserved Allogeneic Bone Marrow-Derived Human Mesenchymal Stem Cells will be administered intravenously.
Placebo, with excipients, will be administered intravenously.
The reduction in days on mechanical ventilation, or renal replacement therapy, or vasopressors.
The number of days free from each of these support measures.
Time frame: Through to 28 days post-randomization
Incidence of treatment-emergent adverse events (Safety and tolerability)
Time frame: Through to 28 days post-randomization
Biological endpoints as markers of vascular permeability
Marker of vascular permeability (ex: Ang1 and 2), acute renal injury (ex: Urine TIMP2-IGFBP7, IL-18), muscle weakness (ex: micro RNA (miRNA) growth Differentiation Factor-15 and miR-181a)), mechanisms related to pathogen clearance (ex: cathelicidin, LL-37), and pro and anti-inflammatory cytokines (ex: IL-6, IL-8, IL-10, IL-1B and IL1-RA) related to potential MSC biological effects
Time frame: At baseline, 1, 2, 3 and 7 days post-randomization
Mortality
All-cause mortality
Time frame: Through to 12 months post-randomization
Organ Failure Scores
Sequential Organ Failure Assessment (SOFA) Score
Time frame: Through to 90 days post-randomization
Organ Support Measures
Duration of mechanical ventilation and/or vasopressor agents and/or dialysis/renal replacement therapy
Time frame: Through to 90 days post-randomization
Length of ICU Stay (in days)
Time in ICU
Time frame: Number of elapsed days from admission until ICU discharge, up to one year
Length of Hospital Stay (in days)
Time in Hospital
Time frame: Number of elapsed days from admission until hospital discharge, up to one year
Hospital Re-Admissions
Time frame: At 28 days, 3 and 12 months post-randomization
Patient Reported Outcomes-FIM
Functional Independence Measure (FIM)
Time frame: 7 days and 6 months post-ICU discharge
Patient Reported Outcomes-SF 36
SF-36 Score
Time frame: 7 days and 6 months post-ICU discharge
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