Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Биопрепарат Allogeneic umbilical cord-derived human mesenchymal stromal cells
  Intravenous infusion of 300 million allogeneic, cryopreserved, umbilical cord-derived human mesenchymal stromal cells
• Другое Placebo
  Intravenous infusion of placebo, with excipients

Первичные конечные точки

• Days free from mechanical ventilation and/or vasopressors and/or renal replacement therapy [Срок оценки: Through to 28 days post-randomization]

Вторичные конечные точки (12)

• Biomarkers - Vascular permeability [Срок оценки: At baseline, 1, 3 and 7 days post-randomization]
• Biomarkers - Acute kidney injury [Срок оценки: At baseline, 1, 3 and 7 days post-randomization]
• Biomarkers - Muscle weakness [Срок оценки: At baseline, 1, 3 and 7 days post-randomization]
• Biomarkers - Pathogen clearance [Срок оценки: At baseline, 1, 3 and 7 days post-randomization]
• Biomarkers - Inflammatory mediators and cytokines [Срок оценки: At baseline, 1, 3 and 7 days post-randomization]
• Safety - Adverse Event [Срок оценки: Through to 7 days post-randomization]
• Safety - Serious and Unexpected Adverse Events [Срок оценки: Through to 28 days post-randomization]
• Safety - Expected Adverse Events [Срок оценки: Through to 28 days post-randomization]
• Mortality [Срок оценки: 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) [Срок оценки: Number of elapsed days from admission until ICU discharge, up to 1 year]
• Length of Hospital Stay (in days) [Срок оценки: Number of elapsed days from admission until hospital discharge, up to 1 year]
• Hospital Re-Admissions [Срок оценки: At 28 days, 90 days and 1 year post-randomization]

Критерии участия

Критерии включения

A participant must meet all the following inclusion criteria at time of randomization 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 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
• 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 meeting the eligibility criteria.

Критерии исключения

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

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Канада · 2 центра

• The Ottawa Hospital (General Campus) — Ottawa
• The Ottawa Hospital (Civic Campus) — Ottawa

Идентификаторы

NCT: NCT05969275 · UC-CISSII

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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