Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock

Phase 2

Recruiting

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

• Registration Number: NCT05969275
• Lead Sponsor: Ottawa Hospital Research Institute

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.

Study Timeline

• Study First Submitted: 2023-07-12
• Study First Submitted QC: 2023-07-22
• Study First Posted: 2023-08-01
• Study Start: 2024-02-14
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-04
• Last Update Posted: 2024-12-05
• Primary Completion: 2026-09-30
• Study Completion: 2027-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 296

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Intravenous infusion of placebo, with excipients
Umbilical Cord Mesenchymal Stromal Cells (UC-MSCs)	Allogeneic umbilical cord-derived human mesenchymal stromal cells	Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells

Primary Outcome Measures

Name	Time	Method
Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy	Through to 28 days post-randomization	The number of days free from each of these support measures

Secondary Outcome Measures

Name	Time	Method
Hospital Re-Admissions	At 28 days, 90 days and 1 year post-randomization	Re-admission to any hospital
Biomarkers - Vascular permeability	At baseline, 1, 3 and 7 days post-randomization	Markers of vascular permeability (ex: Angpt1 and 2)
Biomarkers - Muscle weakness	At baseline, 1, 3 and 7 days post-randomization	Markers of muscle weakness (ex: micro RNA \[miR\] miR-181a, growth differentiation Factor-15)
Health Economic Analysis	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
Biomarkers - Pathogen clearance	At baseline, 1, 3 and 7 days post-randomization	Mechanisms related to pathogen clearance (ex: cathelicidin, LL-37)
Biomarkers - Inflammatory mediators and cytokines	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)
Safety - Expected Adverse Events	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)
Length of ICU Stay (in days)	Number of elapsed days from admission until ICU discharge, up to 1 year	Time in ICU
Days free from renal replacement therapy	Through to 90 days post-randomization	Number of days free from renal replacement therapy
Patient Reported Outcomes - Functional Independence Measure (FIM)	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)
Biomarkers - Acute kidney injury	At baseline, 1, 3 and 7 days post-randomization	Markers of acute kidney injury (ex: Urine TIMP2-IGFBP7, IL-18)
Safety - Adverse Event	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
Safety - Serious and Unexpected Adverse Events	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
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	All-cause mortality
ICU Re-Admissions	During index study hospital admission (through study completion, up to 1 year)	Re-admission to ICU during study hospital admission
Organ Failure Rates	Through to 90 days post-randomization	Organ failure rates (using Sequential Organ Failure Assessment Score), described individually and in composite
Days free from vasopressors	Through to 90 days post-randomization	Number of days free from vasopressor agents
Days free from mechanical ventilation	Through to 90 days post-randomization	Number of days free from mechanical ventilation
Length of Hospital Stay (in days)	Number of elapsed days from admission until hospital discharge, up to 1 year	Time in hospital
Patient Reported Outcomes - Short Form Survey-36 (SF-36)	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)

Trial Locations

Locations (2)

The Ottawa Hospital (General Campus); 🇨🇦 Ottawa, Ontario, Canada

The Ottawa Hospital (Civic Campus); 🇨🇦 Ottawa, Ontario, Canada