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REAnimation Low Immune Status Markers (REALISM)

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ClinicalTrials.gov Identifier: NCT02638779
Recruitment Status : Completed
First Posted : December 23, 2015
Last Update Posted : September 17, 2018
Sponsor:
Collaborators:
Bioaster
BioMérieux
Sanofi
Information provided by (Responsible Party):
Hospices Civils de Lyon

Brief Summary:

The fact that sepsis disrupts immune system homeostasis by inducing an initial cytokine storm, that participates to occurrence of organ failures and early death, followed by a compensatory anti-inflammatory response leading to immunosuppression, is now well established. This immunomodulating response results in a higher risk of secondary infections and is associated to 2/3 of deaths related to septic shocks. Follow up of patients' immune status with time is crucial to guide therapy management. Objective of REALISM project is to demonstrate existence of this immunosuppression phase, by providing strong epidemiologic data for septic shock patients, but also by extension to other situations of inflammatory aggressions like severe severe trauma or burns, or major surgery. This project will provide tools to predict occurrence of secondary infections and guide patient management by comparing innovating immunomonitoring tools to reference tests non already adapted to a routine patient management.

Targeted populations are adult patients hospitalized for septic shock, severe trauma (including severe burn) or major surgery and healthy volunteers, whom blood samples will serve to validate reference intervals of the two reference tests.


Condition or disease Intervention/treatment Phase
Septic Shock Severe Trauma Severe Burn Major Surgery Biological: Blood sampling Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 552 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: REAnimation Low Immune Status Markers
Actual Study Start Date : December 11, 2015
Actual Primary Completion Date : June 27, 2018
Actual Study Completion Date : June 27, 2018

Arm Intervention/treatment
Experimental: Blood sampling
Blood sampling will be performed in all patients and healthy volunteers
Biological: Blood sampling
Specific Blood sampling will be performed in patients and healthy volunteers




Primary Outcome Measures :
  1. Percentage of patients meeting the definition of of injury-induced-immunosuppression [ Time Frame: Up to 2 months after injury ]
    The immunosuppression status will be determined from two immunological reference tests: (1) lymphocyte proliferation in response to ex vivo T cell stimulation (adaptive immunity) (Poujol et al., 2014) and (2) the production of tumor necrosis factor (TNF) by monocytes in response to ex vivo stimulation by lipopolysaccharide (LPS) (innate immunity) (Duffy et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals (RI) derived from an independent set of healthy volunteers. For this purpose, the definition of immunosuppression will be: an abnormal result in at least one of the two "reference" tests (outside the reference intervals defining normal values), and on at least two consecutive samples. The same reference test must be abnormal in two successive samples examined for the patient to be considered immunosuppressed.


Secondary Outcome Measures :
  1. Proportion of patients with a deficiency of the innate or adaptive immunity [ Time Frame: Up to 2 months after injury ]

    Intensity of the innate immune deficiency will be measured using the production of TNF by monocytes in response to ex vivo stimulation by LPS (Duffy et al., 2014). Intensity of the adaptive immune deficiency will be measured using the lymphocyte proliferation in response to ex vivo T cell stimulation (Poujol et al., 2014). The values measured will be defined as normal or abnormal, depending on whether they are within reference intervals derived from an independent set of healthy volunteers. We will describe for all groups of patients:

    • The proportion of patients with a deficiency of the innate immunity, defined by an abnormal TNF secretion test result after LPS stimulation, for at least two consecutive samples.
    • The proportion of patients with a deficiency of the adaptive immunity, defined by an abnormal lymphocyte proliferation, for at least two consecutive samples.
    • The proportion of patients with at least one abnormal test on Days 1, 3-4, 5-7, 13/18, 26/36 and 52/68

  2. Comparison of performance of the reference tests and new biomarkers for the diagnosis of immunosuppression [ Time Frame: Up to one week after injury ]
    Reference tests being non-standardized and cumbersome to implement, and time to results being incompatible with clinical practice, the use of simpler and quicker tests, based on the use of new biomarkers, would allow the individualization of patient management based on the patient's immune status. One of the secondary objectives is to evaluate the performance of new biomarkers compared to the two reference tests to diagnose immunosuppression. Different types of markers and tests will be evaluated: Viral reactivation markers, host-response markers, immune functional assays, immunophenotyping.

  3. Correlation between the immunosuppression status and the incidence of healthcare-associated infections [ Time Frame: Up to 28 days after injury ]
    To evaluate the association between the immunosuppression status as defined in primary objective and the occurrence of secondary infections related to healthcare, the association of the immunosuppression status upon the occurrence of secondary infection will be examined first, and secondly any possible association between the levels of each of the reference tests and the occurrence of secondary infections will be characterized. In this analysis, a secondary infection related to healthcare will be defined as an infection occurring after inclusion in the study, between inclusion and day 28.

  4. Correlation between immunosuppression and mortality [ Time Frame: Up to 90 days after injury ]
    We will examine the association between immunosuppression (as defined in the primary objective) and in-hospital mortality. Association will be evaluated par measuring occurrence of mortality at days 14, 28, 60 and 90, in the different groups.

  5. Comparison of immune status before and after surgery in the population of surgical patients [ Time Frame: Up to 2 months after surgery ]
    The possibility of taking a sample before surgical stress should allow measurements of the impact of the procedure on the host response, and especially on any subsequent onset of immunosuppression. Oncological pathologies and treatments implemented prior to surgery may also be associated with immunosuppression, and for this reason patients hospitalized for cancer surgery will be compared to those hospitalized for vascular surgery. Impact of surgery on immunosuppression will be measured by comparing immune status as defined by the reference tests, in the population of surgical patients before and after surgery.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria for patients

  • Patient or next of kin having been informed of the conditions of the study and having signed the informed consent form
  • Patient hospitalized for :

    • Septic shock
    • Severe trauma (including severe burn)
    • Major surgery

Inclusion criteria for healthy volunteers

  • Normal clinical examination
  • Signed informed consent form
  • Person with social security insurance

Exclusion criteria for patients

  • Patient with severe neutropenia (neutrophil count <0.5 g/l)
  • Patients receiving immunosuppressive therapy
  • Patients receiving corticosteroids (IV or Per os)
  • Use of therapeutic antibodies
  • Hematological disease under treatment, or treated within 5 years before inclusion
  • End of chemotherapy within the 6 months prior to inclusion
  • Patient with innate or acquired immune deficiency (for example severe combined immunodeficiency, HIV or AIDS, any stage)
  • Patients for whom a care limitation was pronounced at time of enrolment
  • Anticipated length of stay before discharge from the ICU is estimated at less than 48 hours
  • Participation in an intervention study
  • Extra-corporeal circulation in the month preceding inclusion in case of cardiac surgery
  • Pregnant or breastfeeding women
  • Patient with no social security insurance, with restricted liberty or under legal protection

Exclusion criteria for healthy volunteers

  • Person with an infectious syndrome during the last 90 days
  • Extreme physical stress within the last week
  • Person having received within the last 90 days, a treatment based on

    • Antivirals
    • Antibiotics
    • Antiparasitics
    • Antifungics
  • Person having received within the last 15 days, a treatment based on non-steroidal anti-inflammatory drugs (NSAIDs)
  • Person having received within the last 24 months, a treatment based on

    • Immunosuppressive therapy
    • Corticosteroids (IV or Per os)
    • Therapeutic antibodies
    • Chemotherapy
  • History of :

    • innate or acquired immune deficiency
    • Hematological disease
    • Solid tumor
    • Severe chronic disease
    • Surgery or hospitalization within the last 2 years
    • Pregnancy within the last year
  • Participation to a phase I clinical assay during the last year
  • Pregnant or breastfeeding women
  • Person with restricted liberty or under legal protection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02638779


Locations
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France
Service d'Anesthésie Réanimation - Hôpital Edouard Herriot
LYON cedex 03, France, 69437
Sponsors and Collaborators
Hospices Civils de Lyon
Bioaster
BioMérieux
Sanofi

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT02638779     History of Changes
Other Study ID Numbers: 69HCL15_0379
2015-A01293-46 ( Other Identifier: ID-RCB )
First Posted: December 23, 2015    Key Record Dates
Last Update Posted: September 17, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Hospices Civils de Lyon:
Septic shock
severe trauma
severe burn
major surgery
immunosuppression
Healthcare-Associated Infections
Additional relevant MeSH terms:
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Shock, Septic
Shock
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation