Clinical trial NCT05969275: Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock
Official title: Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock: A Multi-Center, Double Blind, Phase II Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Septic Shock
Sepsis
Pathologic Processes
Shock
Systemic Inflammatory Response Syndrome
Inflammation
Infections
Keywords: Mesenchymal Stem Cells
Mesenchymal Stromal Cells
Randomized Controlled Trial
Cryopreserved
Allogeneic
Umbilical Cord
Phase II
Sepsis
Septic Shock
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Stem Cell Network
name: Canadian Critical Care Trials Group
name: Technische Universität Dresden
First posted: 2023-08-01
Enrollment: 296
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Controlled Trial
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

A participant must meet all the following inclusion criteria at time of randomization to be eligible:

1. At least 18 years of age AND
2. Requirement for admission to the intensive care unit AND
3. Index admission to the intensive care unit AND
4. 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
5. Clinician impression that cardiovascular organ failure is related to infection AND
6. 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:

   1. 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
   2. Hematological failure: platelet count of \</= 100 X 10\^9/L OR
   3. 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
   4. 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.

Exclusion Criteria:

Patients will be excluded if they have at least one of the following at time of randomization:

1. Another form of shock (cardiogenic, hypovolemic, obstructive) OR
2. History of known chronic pulmonary hypertension with a WHO functional class of IV OR
3. History of severe chronic pulmonary disease requiring home oxygen OR
4. 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
5. History of severe chronic liver disease (Child-Pugh Class C or model for end stage liver disease (MELD) Score \>= 15) OR
6. Malignancy in previous 1 year (excluding resolved non-melanoma skin cancer) OR
7. Treating physician impression that death is imminent within the 12 hours after meeting eligibility criteria OR
8. Pregnant or lactating OR
9. Family or patient not committed to aggressive care

Primary outcomes:
measure: Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy
timeFrame: Through to 28 days post-randomization
Secondary outcomes:
measure: Biomarkers - Vascular permeability
timeFrame: At baseline, 1, 3 and 7 days post-randomization
measure: Biomarkers - Acute kidney injury
timeFrame: At baseline, 1, 3 and 7 days post-randomization
measure: Biomarkers - Muscle weakness
timeFrame: At baseline, 1, 3 and 7 days post-randomization
measure: Biomarkers - Pathogen clearance
timeFrame: At baseline, 1, 3 and 7 days post-randomization
measure: Biomarkers - Inflammatory mediators and cytokines
timeFrame: At baseline, 1, 3 and 7 days post-randomization
measure: Safety - Adverse Event
timeFrame: Through to 7 days post-randomization
measure: Safety - Serious and Unexpected Adverse Events
timeFrame: Through to 28 days post-randomization
measure: Safety - Expected Adverse Events
timeFrame: Through to 28 days post-randomization
measure: Mortality
timeFrame: 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
measure: Length of ICU Stay (in days)
timeFrame: Number of elapsed days from admission until ICU discharge, up to 1 year
measure: Length of Hospital Stay (in days)
timeFrame: Number of elapsed days from admission until hospital discharge, up to 1 year
measure: Hospital Re-Admissions
timeFrame: At 28 days, 90 days and 1 year post-randomization
measure: ICU Re-Admissions
timeFrame: During index study hospital admission (through study completion, up to 1 year)
measure: Organ Failure Rates
timeFrame: Through to 90 days post-randomization
measure: Days free from mechanical ventilation
timeFrame: Through to 90 days post-randomization
measure: Days free from vasopressors
timeFrame: Through to 90 days post-randomization
measure: Days free from renal replacement therapy
timeFrame: Through to 90 days post-randomization
measure: Patient Reported Outcomes - Functional Independence Measure (FIM)
timeFrame: At 30 days, 6 months and 1 year post-randomization
measure: Patient Reported Outcomes - Short Form Survey-36 (SF-36)
timeFrame: At 30 days, 6 months and 1 year post-randomization
measure: Health Economic Analysis
timeFrame: Through to 28 days post-randomization
Other outcomes:
Locations:
city: Ottawa
country: Canada
facility: The Ottawa Hospital (General Campus)
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital (Civic Campus)
state: Ontario
Study officials:
affiliation: The Ottawa Hospital Research Institute
name: Lauralyn McIntyre, MD
role: PRINCIPAL_INVESTIGATOR
References: