Trial document





This trial has been registered retrospectively.
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  DRKS00000505

Trial Description

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Title

The different isoforms of the receptor for advanced glycation endproducts as key points in the septic immune response

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Trial Acronym

RAMMSES-Trial

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Aim of this study is to characterise in detail the various isoforms of "Receptor for Advanced Glycation Endproducts (RAGE)" as new forms of receptors in the human sepsis. Furthermore, investigations are to be carried out to find out the connection between oxidative stress, carbonyl-stress, RAGE-expression and the NFκB-activation within the field of human sepsis. Simultaneously, the modulation of coagulation during the ongoing inflammatory process shall also be evaluated.

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Brief Summary in Scientific Language

Aim of the actual study is to now characterise the human RAGE during sepsis. This especially includes differentiation of specific subvariants (esRAGE/cleaved sRAGE) of soluble receptors (total sRAGE), their kinetics and relevance within the scope of inflammatory events, as well as understanding the signal transduction paths of the cell-bound and the soluble variations. Furthermore, the diagnostic and prognostic parameters, esRAGE/cleaved sRAGE, should be checked on patients suffering of severe sepsis and septic shock. During evaluation of the RAGE-dependent signal transduction the transcription factor, Nuclear Factor kappa B (NFκB), should above all stand in focus of interest, since the Receptor for Advanced Glycation Endproduct (RAGE) induces a distinctive increase of the new synthesis of pro-inflammatory effective p65-subunit of the NFκB-molecule. An inadequate increase and/or prolonged NFκB-activation with consecutive overexpression of NFκB-dependent mediator proteins contribute considerably to the devastating effects of septic immune response. Starting point of a RAGE-dependent perpetuation is always an inflammatory stimulus, which leads to an initial NFκB-activation via an intermittently charged signal cascade or via induction of oxidative stress (OS: Reactive Oxygen Species / RNS: Reactive Nitrogen Species), respectively carbonyl stress (Methylglyoxal, Glucoson, Desoyglucoson). This subsequently mediates a consecutively enhanced RAGE-expression with secondary, RAGE-mediated perpetuation of the NFκB-p65-activation. In addition, in the case of the carbonyl stresses, Advanced Gylcation Endproducts (AGEs) are also generated, which are now increasingly available as RAGE-ligands. In turn, the increased RAGE-ligand-interaction leads to an enhanced availability of transcriptional active NFκB-p65, which induces pro-inflammatory effects. Moreover, RAGE suppresses the expression of carbonyl-stress detoxified enzymes (gyloxalase-I), which, in turn, leads to an aggravation of the carbonyl-stress with consecutive increased generation of AGEs. A vicious circle seems to develop within the field of septic immune response. Further clarification of the problem could contribute to a better clinical and pathological understanding of sepsis and its diagnosis.
A further interesting aspect of this project is the tight link between inflammation and haemostasis (thrombocytic, plasmatic). The ongoing inflammatory reaction during sepsis activates not only the immune systems but also the coagulation system - locally and systemically. This disseminated coagulation activation with simultaneous fibrinolysis inhibition leads to formation of disseminated, microvascular thrombosis and promotes the occurrence of microcirculatory disturbances. Due to parenchymatic hypoperfusion, these contribute considerably to the development of the much feared septic multi organ failure (MOF). Furthermore, the distinctive use of coagulation factors and thrombocytes causes simultaneous tendency to bleed in septic patients. This clinical paradoxon is called Disseminated Intravascular Coagulation (DIC).
In a prospective clinical study concerning 60 patients with severe sepsis or septic shock according to the consensus conference criteria of the ACCP/SCCM in 2001, the following parameters were determined on day 0-1-4-7-14-28: laboratory parameter, hemodynamics, respiration, blood gas, metabolics, balancing and evaluating the severity of the disease by daily ascertainment of APACHE II-, SOFA-, SAPA- and DIC-scores. Additional measurements were not necessary, since it concerned normal circulation and routine blood parameters in critically ill patients.
Determining esRAGE, total SRAGE, S100, AGEs, HMGB 1, IL-1, IL-t, IL-8, TNF-α, MIF, TRX, MnSOD, GSH, TAC as well as MPO via ELISA technique, the flow cytometric determination of TLRs, RAGE, TREM-1 and HLA-DR, the determination of plasmatic concentration of methylglyoxal via "Reverse-Phase"-HPLC as well as the spectrophotometric registration of Glyoxalase-I-activity in Plasma all require additional blood samples of approx. 3 ml each during routine withdrawal. In order to yield/extract human mononuclear cells (Peripheral Blood Mononuclear Cells/PBMCs), blood is withdrawn three times per day (day 0-1-7) in addition to routine samples. At the same time, a further haemostatic monitoring is performed via modern "Point-of-Care"-equipment (ROTEM®, Mulitplate®, PFA-100®,). For this purpose, approx. 3 ml of blood each is additionally withdrawn on day 0-1-4-7-14-28. Therefore, the total amount of blood withdrawn per patient over a period of 4 Weeks is 96ml. Also, 90 days after start of illness, an Outcom-Reevaluation is performed and, if applicable, patients or their physicians are contacted.
30 healthy subjects and 30 patients with major visceral surgical operations (e.g. pancreatic left-side resection, pp-Whipple, total pancreatecomie, hemihepatectomie and oesophageal resection) serve as the control group.

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Organizational Data

  •   DRKS00000505
  •   2010/11/08
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  •   yes
  •   Approved
  •   S123-2009, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

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Health Condition or Problem studied

  •   A41.9 -  Septicaemia, unspecified
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Interventions/Observational Groups

  •   Patients with septic shock
  •   Patients following major abdominal surgery
  •   Healthy volunteers
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Characteristics

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

Survival

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Secondary Outcome

Disease Severity

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2009/08/03
  •   120
  •   Monocenter trial
  •   National
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Inclusion Criteria

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

Sepsis criteria according to international guidelines

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Exclusion Criteria

Not meeting the inclusion criteria
- Refusing study participation
- Pre-existing renal disease
- Rheumatoid arthritis
- M. Alzheimer
- Inflammatory bowel disease
- Chronic pancreatitis
- Arteriosclerosis with preceding myocardial ischemia

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Addresses

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Sources of Monetary or Material Support

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    • Klinik für Anaesthesie Uniklinkum Heidelberg
    • INF 110
    • 69120  Heidelberg
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2010/10/28
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.