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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Septic Shock
• Intervention / Treatment: Biological: Allogeneic umbilical cord-derived human mesenchymal stromal cells; Other: Placebo

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 Type: Interventional
• Enrollment (Estimated): 296
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Josee Champagne; Phone Number: 73836 613-737-8899; Email: UCCISS@ohri.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • The Ottawa Hospital (General Campus)
      • Contact: Irene Watpool, RN; Email: UCCISS@ohri.ca
      • Principal Investigator: Lauralyn McIntyre, MD
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Recruiting
      • The Ottawa Hospital (Civic Campus)
      • Principal Investigator: Lauralyn McIntyre, MD
      • Contact: Rebecca Porteous, RN; Email: UCCISS@ohri.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Technische Universität Dresden; Canadian Critical Care Trials Group; Stem Cell Network
• Investigators: Principal Investigator: Lauralyn McIntyre, MD, The Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2024
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: July 12, 2023
• First Submitted That Met QC Criteria: July 22, 2023
• First Posted (Actual): August 1, 2023

Study Record Updates

• Last Update Posted (Estimated): December 5, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Septic Shock; Mesenchymal Stem Cells; Sepsis; Allogeneic; Phase II; Mesenchymal Stromal Cells; Cryopreserved; Umbilical Cord
• Additional Relevant MeSH Terms: Infections; Sepsis; Inflammation; Pathologic Processes; Shock; Shock, Septic; Systemic Inflammatory Response Syndrome
• Other Study ID Numbers: UC-CISSII

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No