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

• ClinicalTrials.gov Identifier: NCT05969275
• Recruitment Status: Recruiting
• First Posted: August 1, 2023
• Last Update Posted: February 15, 2024
• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Stem Cell Network; Canadian Critical Care Trials Group; Technische Universität Dresden
• Information provided by (Responsible Party): Ottawa Hospital Research Institute

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).

Condition or disease	Intervention/treatment	Phase
Septic Shock; Sepsis; Pathologic Processes; Shock; Systemic Inflammatory Response Syndrome; Inflammation; Infections	Biological: Allogeneic umbilical cord-derived human mesenchymal stromal cells; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 296 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized Controlled Trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-Blind
• Primary Purpose: Treatment
• Official Title: Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock: A Multi-Center, Double Blind, Phase II Randomized Controlled Trial
• Actual Study Start Date: February 14, 2024
• Estimated Primary Completion Date: September 30, 2026
• Estimated Study Completion Date: March 31, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs); Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells	Biological: Allogeneic umbilical cord-derived human mesenchymal stromal cells; Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells
Placebo Comparator: Placebo; Intravenous infusion of placebo, with excipients	Other: Placebo; Intravenous infusion of placebo, with excipients

Outcome Measures

Primary Outcome Measures :

1. Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy [ Time Frame: Through to 28 days post-randomization ]
   The number of days free from each of these support measures

Secondary Outcome Measures :

1. Biomarkers - Vascular permeability [ Time Frame: At baseline, 1, 3 and 7 days post-randomization ]
   Markers of vascular permeability (ex: Angpt1 and 2)
2. Biomarkers - Acute kidney injury [ Time Frame: At baseline, 1, 3 and 7 days post-randomization ]
   Markers of acute kidney injury (ex: Urine TIMP2-IGFBP7, IL-18)
3. Biomarkers - Muscle weakness [ Time Frame: At baseline, 1, 3 and 7 days post-randomization ]
   Markers of muscle weakness (ex: micro RNA [miR] miR-181a, growth differentiation Factor-15)
4. Biomarkers - Pathogen clearance [ Time Frame: At baseline, 1, 3 and 7 days post-randomization ]
   Mechanisms related to pathogen clearance (ex: cathelicidin, LL-37)
5. Biomarkers - Inflammatory mediators and cytokines [ Time Frame: At baseline, 1, 3 and 7 days post-randomization ]
   Pro- and anti-inflammatory mediators and cytokines (ex: CRP, IL-6, IL-8, IL-10, IL-1B and IL1-RA)
6. Safety - Adverse Event [ Time Frame: Through to 7 days post-randomization ]
   Safety of study treatment administration, examined for the occurrence of any adverse event (which requires treatment or intervention) regardless of relationship to study treatment
7. Safety - Serious and Unexpected Adverse Events [ Time Frame: Through to 28 days post-randomization ]
   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
8. Safety - Expected Adverse Events [ Time Frame: Through to 28 days post-randomization ]
   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)
9. 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 ]
   All-cause mortality
10. Length of ICU Stay (in days) [ Time Frame: Number of elapsed days from admission until ICU discharge, up to 1 year ]
    Time in ICU
11. Length of Hospital Stay (in days) [ Time Frame: Number of elapsed days from admission until hospital discharge, up to 1 year ]
    Time in hospital
12. Hospital Re-Admissions [ Time Frame: At 28 days, 90 days and 1 year post-randomization ]
    Re-admission to any hospital
13. ICU Re-Admissions [ Time Frame: During index study hospital admission (through study completion, up to 1 year) ]
    Re-admission to ICU during study hospital admission
14. Organ Failure Rates [ Time Frame: Through to 90 days post-randomization ]
    Organ failure rates (using Sequential Organ Failure Assessment Score), described individually and in composite
15. Days free from mechanical ventilation [ Time Frame: Through to 90 days post-randomization ]
    Number of days free from mechanical ventilation
16. Days free from vasopressors [ Time Frame: Through to 90 days post-randomization ]
    Number of days free from vasopressor agents
17. Days free from renal replacement therapy [ Time Frame: Through to 90 days post-randomization ]
    Number of days free from renal replacement therapy
18. Patient Reported Outcomes - Functional Independence Measure (FIM) [ Time Frame: At 30 days, 6 months and 1 year post-randomization ]
    FIM scores ranging from 18 to 126 (where the higher the score, the more independent the patient is)
19. Patient Reported Outcomes - Short Form Survey-36 (SF-36) [ Time Frame: At 30 days, 6 months and 1 year post-randomization ]
    SF-36 scores ranging from 0 to 100 (with higher scores indicating better health status)
20. Health Economic Analysis [ Time Frame: Through to 28 days post-randomization ]
    A cost-utility analysis of MSCs compared to placebo from a perspective of Canada's publicly funded health care system will be conducted

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

A participant must meet all the following inclusion criteria 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, 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
   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 admission to the ICU.

Exclusion Criteria:

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

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

Contacts and Locations

Contacts

Contact: Josee Champagne; 613-737-8899 ext 73836; UCCISS@ohri.ca

Locations

Canada, Ontario

The Ottawa Hospital (General Campus); Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Contact: Irene Watpool, RN UCCISS@ohri.ca

Principal Investigator: Lauralyn McIntyre, MD

The Ottawa Hospital (Civic Campus); Recruiting

Ottawa, Ontario, Canada, K1Y 4E9

Contact: Rebecca Porteous, RN UCCISS@ohri.ca

Principal Investigator: Lauralyn McIntyre, MD

Sponsors and Collaborators

Ottawa Hospital Research Institute

Canadian Institutes of Health Research (CIHR)

Stem Cell Network

Canadian Critical Care Trials Group

Technische Universität Dresden

Investigators

• Principal Investigator: Lauralyn McIntyre, MD; The Ottawa Hospital Research Institute

More Information

• Responsible Party: Ottawa Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT05969275
• Other Study ID Numbers: UC-CISSII
• First Posted: August 1, 2023
• Last Update Posted: February 15, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ottawa Hospital Research Institute:

Mesenchymal Stem Cells; Mesenchymal Stromal Cells; Randomized Controlled Trial; Cryopreserved; Allogeneic; Umbilical Cord; Phase II; Sepsis; Septic Shock

Additional relevant MeSH terms:

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