Trial document




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  DRKS00003579

Trial Description

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Title

Long-term Immunological Sequelae in Sepsis-Survivors

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Trial Acronym

LOSS

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URL of the Trial

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Brief Summary in Lay Language

Blood toxemia (sepsis) leads to serious and health-threatening alterations of the body´s defense, not only due to the sepsis inducing germ (pathogen), but also secondary to the body´s own hyperresponsiveness to the pathogen. Within this scenario, hyperresponsiveness alternates with failing of the body´s own defense (immunosuppression). Until today, it is not fully understood which parts of the body´s defense are disturbed, however, this has massive impact on the patient´s optimal treatment strategy.
It is further known, that patients having survived sepsis succumb much more often within the next five years than patients without sepsis, despite present co-morbidities.
However, the cause for this long-term mortality has not been fully elucidated so far.
Aim of the present study is to evaluate the immune function of patients having survived sepsis within the first year after the initial event. Obtained data is planned to be compared with data from healthy persons.
This study aims to improve the understanding of nature and extent of sepsis-induced alterations of the immune system and to reveal, whether targeted analysis of distinct parts of the immune system can better characterize the alteration of the body´s defense, thus abridging the diagnosis of imunosuppression and improving and accelerating the initiation of optimal therapeutic measures.
To delineate the impact of blood toxemia on body´s defense from effects caused by the overwhelming inflammatory response, patients with an exuberant inflammatory response of the body due to a non-infectious cause, the so called Systemic Inflammatory Response Syndrome (SIRS), after a surgical procedure, are planned to be examined within this project. For this reason, an amendment of the study protocol was proposed on 08/21/2013, encompassing a third study arm. Thereupon, changes regarding study arms as well as key in- and exclusion criterias were introduced.

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Brief Summary in Scientific Language

After an early phase of over-exuberant inflammatory response, sepsis is characterised by a state of immunosuppression leading to insufficient eradication of the primary infection, the occurrence of secondary infections, or the reactivation of viral infections. Moreover, sepsis results in an increased mortality rate in survivors for years after the acute episode despite present co-morbidities.
Besides alterations in antigen presentation, massive, sepsis-induced lymphocyte apoptosis seems to play a major role in this scenario.
However, it remains elusive, whether this massive sepsis-induced immunosuppression leads to clinically relevant immunological long-term sequelae in terms of reactivation of chronic infections or loss of protection from previous vaccinations, and how reconstitution of the lymphocyte compartment is achieved.
We hypothesize that sepsis induced alterations of innate and adaptive immunity during acute phase of disease lead to clinically relevant immunological long-term consequences.
This study aims to evaluate the nature and extent of sepsis induced immunosuppression by means of a longitudinal clinical observation of sepsis survivors for one year in comparison to healthy controls as well as a group of patients with postoperative SIRS (Systemic Inflammatory Response Syndrome).

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00003579
  •   2012/02/29
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  •   yes
  •   Approved
  •   2835-05/10, Ethikkommission der Friedrich-Schiller-Universität Jena an der Medizinischen Fakultät
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Secondary IDs

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Health Condition or Problem studied

  •   Sepsis
  •   Severe Sepsis
  •   Septic Shock
  •   A41.9 -  Septicaemia, unspecified
  •   R57.2 -  [generalization R57: Shock, not elsewhere classified]
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Interventions/Observational Groups

  •   No intervention. Patients having survived sepsis are diagnostically evaluated regarding their immune function on day 5, 30, 90, 180, and 360 after the initial event.

  •   No intervention. Healthy volunteers serve as a control, being diagnostically evaluated regarding their immune function on day 5, 180, and 360.
  •   No intervention. Patients with postoperative SIRS serve as a control, being diagnostically evaluated regarding their immune function on day 1, 14, 30, and 90.
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Characteristics

  •   Non-interventional
  •   Other
  •   Non-randomized controlled trial
  •   Open (masking not used)
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  •   Other
  •   Basic research/physiological study
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

Inadequate reconstitution of immune function 1,3, 6, and 12 months after sepsis regarding
monocyte HLA-DR expression, evaluated by flow cytometry.

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Secondary Outcome

Evaluation of the suppressed immune function by flow cytometry 1, 3, 6, and 12 months after sepsis regarding lymphocyte function after antigen specific and - unspecific stimulation.

Furthermore, the suppressed immune function will be evaluated based on the following factors:
1. APACHE II Score and SAPS II Score
2. Survival after 1, 3, 6, and 12 months
3. Re-Occurrence of sepsis after 1, 3, 6, and 12 Monaten
4. Immunological characterisation by monocyte HLA-DR expression, lymhocyte compartment composition and response to antigen specific and - unspecific stimulation, including T cell receptor diversity), and neutrophil functionality 4 to 14 days after sepsis onset.
5. Composition of lymphocyte compartment, including T cell receptor diversity), and neutrophil functionality one, three, six, and twelve months after sepsis onset.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2012/03/01
  •   59
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

Key Inclusion Criteria Patient:
1.Sepsis, Severe sepsis, or septic shock based on the definitions by the ACCP/SCCM Consensus Conference:

- Sepsis: SIRS with documented infection
-->SIRS: presence of at least two criteria:
1) body temperature <36°C or >38°C),
2) tachycardia (>90 beats/min),
3) tachypnea (>20 breaths/min or PaCO2< 4.3kPa [32 mmHg], or need for mechanical ventilation),
4) white blood count <4000 cells/µl or >12,000 cells/µl.
--> Infection: defined by the International Sepsis Forum Consensus Conference on Definitions of Infection in the Intensive Care Unit.

-Severe sepsis: sepsis with at least one manifestation of inadequate organ perfusion or function:
1) hypoxemia (PaO2<10kPa),
2) metabolic acidosis (ph<7.30),
3) oliguria (<30 ml/hr),
4) lactic acidosis (serum lactate >2mmol/l),
5) acute alteration in mental status without sedation.

-Septic shock: sepsis with sustained decrease in systolic blood pressure (<90mmHg, or drop of 40 mmHg from baseline) despite fluid resuscitation and need for vasoactive amines to maintain adequate blood pressure.

2. Male or female persons, age =/> 18 years
3. Obtained oral and written consent

Key Inclusion Criteria Healthy Control:
1. Male or female persons, age =/> 18 years
2. Obtained oral and written consent

Key Inclusion Criteria SIRS Control:
1. SIRS based on the definitions by the ACCP/SCCM Consensus Conference:
-->SIRS: presence of at least two criteria:
1) body temperature <36°C or >38°C),
2) tachycardia (>90 beats/min),
3) tachypnea (>20 breaths/min or PaCO2< 4.3kPa [32 mmHg], or need for mechanical ventilation),
4) white blood count <4000 cells/µl or >12,000 cells/µl.

2. Male or female persons, age =/> 18 years
3. Obtained oral and written consent

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Exclusion Criteria

Key Exclusion Criteria Patient:
1. Systemic autoimmune disease, malignant hemopathy, HIV infection, transplantation, immunosuppressive medication (corticosteroids with >10mg prednisolone equivalent/day)
2. Chemo- or radiotherapy due to malignancy
3. End-stage chronic liver disease (Child-Pugh C)
4. End-stage chronic kidney disease (requiring renal replacement therapy)
5. Extracorporeal circulation and/or membrane oxygenation
6. Ischemic stroke or intracranial bleeding within last three months
7. Pregnancy and nursing
8. Participation in interventional study

Key Exclusion Criteria Healthy Control:
1.Sepsis, Severe sepsis, or septic shock based on the definitions by the ACCP/SCCM Consensus Conference at the time of screening or in medical history
2. Systemic autoimmune disease, malignant hemopathy, HIV infection, transplantation, immunosuppressive medication (corticosteroids with >10mg prednisolone equivalent/day)
3. Chemo- or radiotherapy due to malignancy
4. End-stage chronic liver disease (Child-Pugh C)
5. End-stage chronic kidney disease (requiring renal replacement therapy)
6. Extracorporeal circulation and/or membrane oxygenation
7. Ischemic stroke or intracranial bleeding within last three months
8. Pregnancy and nursing
9. Participation in interventional study

Key Exclusion Criteria SIRS Control:
1.Sepsis, Severe sepsis, or septic shock based on the definitions by the ACCP/SCCM Consensus Conference at the time of screening or in medical history
2. Systemic autoimmune disease, malignant hemopathy, HIV infection, transplantation, immunosuppressive medication (corticosteroids with >10mg prednisolone equivalent/day)
3. Chemo- or radiotherapy due to malignancy
4. End-stage chronic liver disease (Child-Pugh C)
5. End-stage chronic kidney disease (requiring renal replacement therapy)
6. Ischemic stroke or intracranial bleeding within last three months
7. Pregnancy and nursing
8. Participation in interventional study

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Addresses

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    • Universitätsklinikum Jena Friedrich-Schiller-Universität Center for Sepsis Control and Care (CSCC)
    • Erlanger Allee 101
    • 07747  Jena
    • Germany
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    • Universitätsklinikum Jena Center for Sepsis Control and Care (CSCC)
    • Ms.  Dr. med.  Katharina  Ferrari-Kühne 
    • Erlanger Allee 101
    • 07747  Jena
    • Germany
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    • Universitätsklinikum Jena Center for Sepsis Control and Care (CSCC)
    • Ms.  Dr. med.   Katharina  Ferrari-Kühne 
    • Erlanger Allee 101
    • 07747  Jena
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Berlin
    • Hannoversche Strasse 28-30
    • 10115  Berlin
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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