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Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock (UC-CISSII)

Primary Purpose

Septic Shock, Sepsis, Pathologic Processes

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Allogeneic umbilical cord-derived human mesenchymal stromal cells
Placebo
Sponsored by
Ottawa Hospital Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring Mesenchymal Stem Cells, Mesenchymal Stromal Cells, Randomized Controlled Trial, Cryopreserved, Allogeneic, Umbilical Cord, Phase II, Sepsis, Septic Shock

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs)

    Placebo

    Arm Description

    Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells

    Intravenous infusion of placebo, with excipients

    Outcomes

    Primary Outcome Measures

    Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy
    The number of days free from each of these support measures

    Secondary Outcome Measures

    Biomarkers - Vascular permeability
    Markers of vascular permeability (ex: Angpt1 and 2)
    Biomarkers - Acute kidney injury
    Markers of acute kidney injury (ex: Urine TIMP2-IGFBP7, IL-18)
    Biomarkers - Muscle weakness
    Markers of muscle weakness (ex: micro RNA [miR] miR-181a, growth differentiation Factor-15)
    Biomarkers - Pathogen clearance
    Mechanisms related to pathogen clearance (ex: cathelicidin, LL-37)
    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)
    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
    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
    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)
    Mortality
    All-cause mortality
    Length of ICU Stay (in days)
    Time in ICU
    Length of Hospital Stay (in days)
    Time in hospital
    Hospital Re-Admissions
    Re-admission to any hospital
    ICU Re-Admissions
    Re-admission to ICU during study hospital admission
    Organ Failure Rates
    Organ failure rates (using Sequential Organ Failure Assessment Score), described individually and in composite
    Days free from mechanical ventilation
    Number of days free from mechanical ventilation
    Days free from vasopressors
    Number of days free from vasopressor agents
    Days free from renal replacement therapy
    Number of days free from renal replacement therapy
    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)
    Patient Reported Outcomes - Short Form Survey-36 (SF-36)
    SF-36 scores ranging from 0 to 100 (with higher scores indicating better health status)
    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

    Full Information

    First Posted
    July 12, 2023
    Last Updated
    August 3, 2023
    Sponsor
    Ottawa Hospital Research Institute
    Collaborators
    Canadian Institutes of Health Research (CIHR), Stem Cell Network, Canadian Critical Care Trials Group, Center for Regenerative Therapies Dresden (CRTD)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05969275
    Brief Title
    Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock
    Acronym
    UC-CISSII
    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

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    August 2023 (Anticipated)
    Primary Completion Date
    March 2026 (Anticipated)
    Study Completion Date
    March 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Ottawa Hospital Research Institute
    Collaborators
    Canadian Institutes of Health Research (CIHR), Stem Cell Network, Canadian Critical Care Trials Group, Center for Regenerative Therapies Dresden (CRTD)

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    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

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Model Description
    Randomized Controlled Trial
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Masking Description
    Double-Blind
    Allocation
    Randomized
    Enrollment
    296 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs)
    Arm Type
    Experimental
    Arm Description
    Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Intravenous infusion of placebo, with excipients
    Intervention Type
    Biological
    Intervention Name(s)
    Allogeneic umbilical cord-derived human mesenchymal stromal cells
    Intervention Description
    Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells
    Intervention Type
    Other
    Intervention Name(s)
    Placebo
    Intervention Description
    Intravenous infusion of placebo, with excipients
    Primary Outcome Measure Information:
    Title
    Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy
    Description
    The number of days free from each of these support measures
    Time Frame
    Through to 28 days post-randomization
    Secondary Outcome Measure Information:
    Title
    Biomarkers - Vascular permeability
    Description
    Markers of vascular permeability (ex: Angpt1 and 2)
    Time Frame
    At baseline, 1, 3 and 7 days post-randomization
    Title
    Biomarkers - Acute kidney injury
    Description
    Markers of acute kidney injury (ex: Urine TIMP2-IGFBP7, IL-18)
    Time Frame
    At baseline, 1, 3 and 7 days post-randomization
    Title
    Biomarkers - Muscle weakness
    Description
    Markers of muscle weakness (ex: micro RNA [miR] miR-181a, growth differentiation Factor-15)
    Time Frame
    At baseline, 1, 3 and 7 days post-randomization
    Title
    Biomarkers - Pathogen clearance
    Description
    Mechanisms related to pathogen clearance (ex: cathelicidin, LL-37)
    Time Frame
    At baseline, 1, 3 and 7 days post-randomization
    Title
    Biomarkers - Inflammatory mediators and cytokines
    Description
    Pro- and anti-inflammatory mediators and cytokines (ex: CRP, IL-6, IL-8, IL-10, IL-1B and IL1-RA)
    Time Frame
    At baseline, 1, 3 and 7 days post-randomization
    Title
    Safety - Adverse Event
    Description
    Safety of study treatment administration, examined for the occurrence of any adverse event (which requires treatment or intervention) regardless of relationship to study treatment
    Time Frame
    Through to 7 days post-randomization
    Title
    Safety - Serious and Unexpected Adverse Events
    Description
    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
    Time Frame
    Through to 28 days post-randomization
    Title
    Safety - Expected Adverse Events
    Description
    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)
    Time Frame
    Through to 28 days post-randomization
    Title
    Mortality
    Description
    All-cause mortality
    Time Frame
    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
    Title
    Length of ICU Stay (in days)
    Description
    Time in ICU
    Time Frame
    Number of elapsed days from admission until ICU discharge, up to 1 year
    Title
    Length of Hospital Stay (in days)
    Description
    Time in hospital
    Time Frame
    Number of elapsed days from admission until hospital discharge, up to 1 year
    Title
    Hospital Re-Admissions
    Description
    Re-admission to any hospital
    Time Frame
    At 28 days, 90 days and 1 year post-randomization
    Title
    ICU Re-Admissions
    Description
    Re-admission to ICU during study hospital admission
    Time Frame
    During index study hospital admission (through study completion, up to 1 year)
    Title
    Organ Failure Rates
    Description
    Organ failure rates (using Sequential Organ Failure Assessment Score), described individually and in composite
    Time Frame
    Through to 90 days post-randomization
    Title
    Days free from mechanical ventilation
    Description
    Number of days free from mechanical ventilation
    Time Frame
    Through to 90 days post-randomization
    Title
    Days free from vasopressors
    Description
    Number of days free from vasopressor agents
    Time Frame
    Through to 90 days post-randomization
    Title
    Days free from renal replacement therapy
    Description
    Number of days free from renal replacement therapy
    Time Frame
    Through to 90 days post-randomization
    Title
    Patient Reported Outcomes - Functional Independence Measure (FIM)
    Description
    FIM scores ranging from 18 to 126 (where the higher the score, the more independent the patient is)
    Time Frame
    At 30 days, 6 months and 1 year post-randomization
    Title
    Patient Reported Outcomes - Short Form Survey-36 (SF-36)
    Description
    SF-36 scores ranging from 0 to 100 (with higher scores indicating better health status)
    Time Frame
    At 30 days, 6 months and 1 year post-randomization
    Title
    Health Economic Analysis
    Description
    A cost-utility analysis of MSCs compared to placebo from a perspective of Canada's publicly funded health care system will be conducted
    Time Frame
    Through to 28 days post-randomization

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Josee Champagne
    Phone
    613-737-8899
    Ext
    73836
    Email
    jochampagne@ohri.ca
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Lauralyn McIntyre, MD
    Organizational Affiliation
    The Ottawa Hospital Research Institute
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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