Russian Clinical Trial of Mesenchymal Cells in Patients With Septic Shock and Severe Neutropenia

Study Overview
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Brief Summary
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Septic shock remains a significant clinical problem associated with high rates of mortality among neutropenic patient despite antimicrobial therapy and supportive care. Recently, mesenchymal stromal cells (MSC) have demonstrated remarkable potential effect in sepsis. MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs reduced systemic inflammatory cytokine levels in mice, down-regulated of inflammation and inflammation-related genes (such as interleukin-10, interleukin-6). Bacterial clearance was greater in MSC-treated mice. Thus, MSCs have beneficial effects on experimental sepsis and suggest that MSСs-therapy may be an effective adjunctive treatment to reduce sepsis-related mortality. The safety of MSCs is proved by Graft-versus-host disease treatment MSCs in patients after bone marrow transplantation. This study hypothesis is that MSCs reduce organ dysfunction/injury, systemic inflammation and mortality in patients with septic shock and severe neutropenia. The main goal of the study is to evaluate the impact of MSCs therapy on organ dysfunction/injury, systemic inflammation and 28-day mortality in patients with septic shock and severe neutropenia. All patients will be randomized in two groups: control group (standard treatment of septic shock) and MSCs-group (standard treatment of septic shock + MSCs infusion of 1-2 millions/kg/ day).

Detailed Description
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All activities related to this human subjects research have been guided by ethical principles and have been reviewed and approved Federalwide Assurance National Ctr for Hematology, FWA00006482. The goal of the trial is to evaluate plasma concentration of proinflammatory cytokine interleukin-6 and the antiinflammatory cytokine interleukin-10, plasma levels of blood creatinine, bilirubin, procalcitonin, C-reactive protein. Then we will evaluate requirement for renal replacement therapy, requirement for mechanical ventilation or non-invasive mechanical ventilation, pulmonary function-coefficient, partial oxygen pressure arterial blood level, electrocardiograms, Kaplan - Meier curve,28-days mortality.

Official Title
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Russian Single-center Open Randomized Clinical Trial of the Impact of Mesenchymal Stromal Cells Therapy on Organ Dysfunction and 28-day Mortality in Patients With Septic Shock and Severe Neutropenia.

Conditions
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Septic Shock, Nonchemotherapy Drug-induced Neutropenia, Neutropenia After Chemotherapy in Oncohematological Patients, Neutropenia in Patients With Aplastic Anemia

Intervention / Treatment
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* Genetic: Mesenchymal stromal cells
* Drug: Standard therapy of septic shock


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: septic shock ≤10 hs after onset of septic shock severe neutropenia(≤ 1 10^9/l) Patients ≥17 years Signed Informed Consent to treatment Exclusion Criteria: oncohematological patients with resistance to chemotherapy Unsigned Informed Consent to treatment Age >75 years; Pregnancy

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard therapy of septic shock<br>according to Surviving Sepsis Campaign 2012 Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids | Drug: Standard therapy of septic shock<br>* Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids<br>|
| Experimental: Mesenchymal stromal cells+ standard therapy of septic shock<br>MSCs intravenous infusion of 1-2 millions/kg/day will be performed not more than 10 hs after onset of septic shock in patients with severe neutropenia(≤ 1x10^9/l). according to Surviving Sepsis Campaign 2012: Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids | Genetic: Mesenchymal stromal cells<br>* MSCs intravenous infusion of 1-2 millions/kg/day will be performed not more than 10 hs after onset of septic shock in patients with severe neutropenia(≤ 1x10^9/l).<br>Drug: Standard therapy of septic shock<br>* Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mortality |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of MSC therapy effects on organ dysfunction | Liver: levels of serum total bilirubin, transaminases, lactate dehydrogenase, plasma protrombin level Pancreas: amylase level Renal: number of hemodialysis/ hemodiafiltration, blood urea and creatinine levels Pulmonary: requirement for mechanical ventilation or non-invasive mechanical ventilation, pulmonary function-coefficient, partial oxygen pressure arterial blood level Cardiac: requirement for vasopressors, main parameters obtained from Transpulmonary Thermodilution- Systemic Vascular Resistance Index ( SVRI ), Cardiac Output (CO) | At Baseline and at day 2,3,7,14,21,28 | 
| Evaluation of MSC therapy effects on systemic inflammatory parameters | plasma concentration of proinflammatory cytokine IL-6 and the antiinflammatory cytokine IL-10, concentration of procalcitonin, C-reactive protein Fibrinogen level, lactate level , the factor XII-dependent fibrinolytic activity blood routine examination | At Baseline and at day 2,3,7,14,21,28 | 
| Evaluation of MSC therapy effects on septic shock reversal | SOFA score | At Baseline and at day 2,3,7,14,21,28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal Stromal Cells, Septic Shock, Neutropenia, Procalcitonin, Interleukin-6, Interleukin-10, C-reactive protein, Survival, Organ dysfunction