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

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.

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).

Study Overview

• Status: Unknown
• Conditions: Septic Shock; Nonchemotherapy Drug-induced Neutropenia; Neutropenia After Chemotherapy in Oncohematological Patients; Neutropenia in Patients With Aplastic Anemia
• Intervention / Treatment: Drug: Standard therapy of septic shock; Genetic: Mesenchymal stromal cells

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 125167
    • Recruiting
    • National Research Center for Hematology
    • Contact: Gennady M Galstyan, MD PhD; Phone Number: +7(495)6124859; Email: gengalst@gmail.com
    • Principal Investigator: : Gennady M. Galstyan,, MD PhD
    • Principal Investigator: Elena N. Parovichnikova, MD,PhD
    • Sub-Investigator: Polina M. Makarova, MD
    • Sub-Investigator: Vyacheslav A. Novikov, MD
    • Sub-Investigator: Irina V. Kolosova, MD
    • Sub-Investigator: Stanislav A. Keselman, MD
    • Sub-Investigator: Alexandr Y. Mashkov, MD
    • Sub-Investigator: Anna V. Krechetova, MD, PhD
    • Sub-Investigator: Dmitri Tihomirov, PhD
    • Sub-Investigator: Tatiana A. Garanzha, PhD
    • Sub-Investigator: Larisa A. Kuzmina, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 75 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard therapy of septic shock; according to Surviving Sepsis Campaign 2012 Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids	Drug: Standard therapy of septic shock; Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids
EXPERIMENTAL: Mesenchymal stromal cells+ standard therapy of septic shock; 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	Drug: Standard therapy of septic shock; Antibiotic therapy Fluid therapy Vasopressors Inotropic therapy Steroids; Genetic: Mesenchymal stromal cells; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Research Center for Hematology, Russia
• Investigators: Principal Investigator: Gennady M. Galstyan, MD PhD, National Research center of Hematology

Publications and helpful links

General Publications

• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.
• Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1047-57. doi: 10.1164/rccm.201001-0010OC. Epub 2010 Jun 17.
• Kebriaei P, Robinson S. Treatment of graft-versus-host-disease with mesenchymal stromal cells. Cytotherapy. 2011 Mar;13(3):262-8. doi: 10.3109/14653249.2010.549688. Epub 2011 Jan 13.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (ACTUAL): April 1, 2013
• Study Completion (ANTICIPATED): May 1, 2015

Study Registration Dates

• First Submitted: May 1, 2013
• First Submitted That Met QC Criteria: May 5, 2013
• First Posted (ESTIMATE): May 8, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): May 10, 2013
• Last Update Submitted That Met QC Criteria: May 8, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Survival; Procalcitonin; Septic Shock; C-reactive protein; Neutropenia; Mesenchymal Stromal Cells; Organ dysfunction; Interleukin-6; Interleukin-10
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bone Marrow Diseases; Hematologic Diseases; Sepsis; Anemia; Agranulocytosis; Leukopenia; Leukocyte Disorders; Bone Marrow Failure Disorders; Shock, Septic; Shock; Neutropenia; Anemia, Aplastic
• Other Study ID Numbers: RuMCeSS