Trial document




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  DRKS00013347

Trial Description

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Title

Identification of cardiovascular and molecular prognostic factors for the mid- and long-term outcome of sepsis

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Trial Acronym

ICROS

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URL of the Trial

https://www.septomics.de/de/translational-septomics.html

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Brief Summary in Lay Language

Sepsis is a life-threatening condition which can affect people of any age. An infection triggers a host response resulting in organ failure. The extent of the organ dysfunction varies between patients and during the course of the condition. Thus far, the only causal treatment option consists in treating the infection early e. g. by an operation or the use of antibiotics. Owing to advances in modern critical care, more patients survive sepsis. Nonetheless, sepsis survivors frequently show impaired organ function, physical disability and considerably decreased health-related quality of life.
It is hypothesized that sepsis-induced cardiac dysfunction – septic cardiomyopathy – may influence mortality. The relationship between occurrence of cardiovascular dysfunction and metabolic changes in the course of sepsis remains unclear. Therefore, the aim of this study is the investigation of cardiovascular function, oxygen consumption and metabolic changes in septic patients. Apart from cardiological routine procedures (echo- and electrocardiography) a newly developed method for measuring the oxygen tension and consumption and bioelectrical impedance analysis for body composition estimation will be employed. Through blood and urine analysis, both routine parameters and parameters focusing on patient metabolism will be analysed.
Septic patients will be assessed in the acute phase (3 and 7 days after sepsis diagnosis), the stable phase (at intensive care unit discharge) and after full or incomplete recovery (during two outpatient visits at 6 and 12 months after sepsis diagnosis). The results will be compared with healthy individuals and patients with existing heart disease (cardiomyopathy).
The study aims to identify clinical parameters and signaling pathways involved in the development and course of sepsis. Furthermore, specific parameters associated with the medium- and long-term health status, physical performance and quality of life after sepsis are to be identified. The overall aim of the study is the development of novel diagnostic and therapeutic approaches in sepsis.

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Brief Summary in Scientific Language

The overall aim of the study is the identification of theragnostic targets for the development of novel diagnostic and therapeutic approaches in sepsis. In sepsis, a dysregulated host response to infection leads to organ failure. The extent of organ dysfunction varies between patients and at different stages of the disease. Advances in modern critical care have reduced 28-day mortality over the last years. Nonetheless, a large proportion of sepsis survivors reports long-term physical, mental and cognitive impairments (post intensive care syndrome) including persistent organ dysfunction (persistent critical illness). In addition, mortality rates are considerably increased up to years after sepsis. However, the underlying molecular mechanisms remain unclear.
There is evidence that the development of septic cardiomyopathy may influence mortality. The relationship between the occurrence of cardiovascular dysfunction and metabolic changes in the course of sepsis has not yet been investigated. Therefore, the key aim of this study is the investigation of cardiovascular function, oxygen consumption and metabolic changes in septic patients. Apart from cardiological routine procedures (echo- and electrocardiography) a newly developed method for measuring the mitochondrial oxygen tension and consumption (COMET) will be applied. As oedema is involved in the pathogenesis of altered microcirculation in sepsis, endothelial dysfunction will be analysed via a set of surrogate parameters and body composition (especially extracellular water) measurement via bioelectrical impedance analysis. In blood, stool and urine, routine parameters and the metabolome, lipidome and microbiome will be analysed. Septic patients will be assessed in the acute phase (3 and 7 days after sepsis diagnosis), the stable phase (at intensive care unit discharge) and after full or incomplete recovery (during two outpatient visits at 6 and 12 months sepsis diagnosis). Analyses will be complemented by in-depth anamnestic and clinical-epidemiological assessment as well as subsequent information on health related quality of life (EQ-5D-3L) and physical performance (6-minute walk test).
The primary endpoint of the study is the difference in mortality rates between septic patients with and without septic cardiomyopathy six months after sepsis diagnosis. Further research questions include differences in clinical and laboratory parameters between these patient groups during the acute phase, and during the mid-, and long-term course.
The results will be compared with healthy individuals and patients with cardiomyopathy in absence of infection.

[Amendment 26.03.2018 and 11.06.2018: modification/extension Arm 2]
[Amendment 14.08.2018: modification Arm 1]
[Amendment 22.08.2019: modification study duration, modification/extension Arm 1-3]
[Amendment 12.12.2019: modification recruitment Arm 1]
[Amendment 20.03.2020: modification Arm 1 for suspected COVID-19]

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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

  •   DRKS00013347
  •   2017/11/30
  •   [---]*
  •   yes
  •   Approved
  •   Vorlagenummer: 5276-09/17 , 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

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

  •   Sepsis (diagnosis septic cardiomyopathy: yes/no):

    Patients without SARS-CoV2 infection
    - Routine and study-specific blood tests (incl. analysis of immune status, metabolites, lipids and mitochondrial DNA) on days 3 ± 24 h (T1) and 7± 24 h (T2) after sepsis diagnosis, at ICU discharge ± 24 h (T3), 6 months ± 2 m (T4) and 12 months ± 2 m after sepsis diagnosis (T5)
    - Echocardiography at T1, T2, T3, T4 and T5
    - Mitochondrial oxygen tension measurement (COMET) at T1, and T3
    - Holter-ECG at T1, T2, T3, T4 and T5
    -Bioimpedanzanalyse: at T1, T2, T3, T4 and T5
    -Microbiome at T2, and T4
    - Transient elastography at T1, T2, T3, T4 and T5

    Patients with suspected or confirmed SARS-CoV2 infection:
    Routine and study-specific blood tests on days 3 ± 24 h (T1) and 7± 24 h (T2) after sepsis diagnosis, at ICU discharge ± 24 h (T3), 6 months ± 2 m (T4) and 12 months ± 2 m after sepsis diagnosis (T5)
    - Echocardiography at T1, T2, T3, T4 and T5 (in a reduced protocol at T1, T2 and T3)
    - Mitochondrial oxygen tension measurement (COMET) at T4 -Holter ECG at T4
    - Bioimpedance analysis at T4 and T5 - Microbiome analysis at T2 and T4
    -Transient elastography at T4 and T5
  •   Cardiomyopathy without infection:
    Patients without operation:
    Analyses upon enrolment (T1):
    - Routine and study-specific blood tests (incl. analysis of immune status, metabolites, lipids and mitochondrial DNA)
    - Echocardiography
    - Mitochondrial oxygen tension measurement (COMET)

    Patients with scheduled LVAD-Implantation:
    - Routine and study-specific blood tests (inlc. analysis of immune Status, metabolites, lipids and mitochondrial DNA), echocardiography before the operation (T0), 7 days post operation (T2), at ICU discharge (T3) and 6 months post operation (T4).
    -analysis of the heart, skeletal muscle and adipose tissue on the day of operation (T1)
    - Mitochondrial oxygen tension measurement (COMET) at T0, T3 and T4
  •   Healthy subjects:
    Analyses upon enrolment (T1)
    - Routine and study-specific blood tests (incl. analysis of immune status, metabolites, lipids and mitochondrial DNA)
    - Echocardiography
    - Mitochondrial oxygen tension measurement (COMET)
    - Holter monitoring
    - Bioimpedance analysis
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Characteristics

  •   Non-interventional
  •   Other
  •   Non-randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Other
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

Difference in mortality rates between septic patients with and without septic cardiomyopathy six months after sepsis diagnosis

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Secondary Outcome

- Difference in mortality rates between septic patients with or without septic cardiomyopathy twelve months after sepsis diagnosis

Estimation of incidence of septic cardiomyopathy in the acute phase of sepsis

To address further research questions, the parameters from the following methods will be analysed: cardiovascular risk-factors and function (echocardiography), body composition (especially extracellular body water, bioelectrical impedance analysis), organ dysfunctions, immune-status, metabolome, lipidome, microbiome, function of the autonomic nervous system (Holter-monitoring), surrogate parameters of cellular oxygen tension and consumption (COMET).

Analysis of the acute and post-acute course of sepsis (all patients and stratified by the presence of septic cardiomyopathy) to explore potential surrogate parameters for the occurence of cardiac dysfunction.

Analysis of potential group differences between septic patients (all patients and stratified by the presence of septic cardiomyopathy) in the acute and post-acute course and control groups (healthy subjects / patients with dilated cardiomyopathy) to identify potential diagnostic parameters.

Analysis of the medium- and long-term course of sepsis (all patients and stratified by the presence of septic cardiomyopathy) to assess the reversibility of organ dysfunction, especially cardiovascular dysfunction.

Analysis of potential group differences between septic patients (all patients and stratified by the presence of septic cardiomyopathy) in the medium- and long-term course and control groups (healthy individuals / patients with dilated cardiomyopathy) to identify potential biomarkers to predict the medium- and long-term course of sepsis. In this context, potential therapeutic aims will be identified and analysed pre-clinically.

Analysis of medium- and long-term morbidity in septic patients (all patients and stratified by the presence of septic cardiomyopathy) by means of physical performance, quality of life (EQ-5D-3L) and performance (6-minute-walking test) as well as type and frequency of cardiovascular events after sepsis-diagnosis and in control groups (healthy subjects / patients with dilated cardiomyopathy).

Analysis of potential predictors for the medium- and long-term mortality and morbidity (quality of life, physical performance) after sepsis. The focus lies on data from the acute and post-acute phase of sepsis.


Characterisation of the pre- (T0), intra- (T1) and post-operative (T2, T3) as well as medium-term (T4) patient status.

Identification of clinical and laboratory-assessed prognostic factors for the short- (T2, T3) and medium-term (T4) morbidity and mortality of patients after LVAD Implantation.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Medical Center 
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Recruitment

  •   Actual
  •   2018/04/15
  •   290
  •   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

Arm 1:
• sepsis or septic shock according to Sepsis-3 criteria
• first infection-associated organ dysfunction (= sepsis diagnosis) no older than 72 hours (first blood sample within 96 hours after sepsis diagnosis)
• age > 18 years
• written informed consent of the patient or his legal representative

Arm 2:
• dilated cardiomyopathy
• age > 18 years
• written informed consent

Arm 3:
• age > 18 years
• written informed consent

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Exclusion Criteria

Arm 1:
• cardiac surgery ≤ 12 months
• significant pre-existing heart condition
o endocarditis
o higher-grade valvular heart disease
(grade 3 valve disease, symptomatic aortic stenosis, medium-degree mitral valve insufficiency with reduced ejection fraction or clinical symptoms)
o complex structural congenital heart condition (TGA, Tetralogy of Fallot, endocardial cushion defect etc.)
o hemodynamic relevant shunt deficit
o pre-existing significantly reduced cardiac performance
(ejection fraction < 45 % or 10 % below norm value)
o pre-existing pulmonary hypertension
o myocardial infarction ≤ 1 year in patient history
o heart transplantation in patient history
• cardiopulmonary resuscitation<4 weeks
• pneumonectomy in medical history
• liver cirrhosis Child C
• contraindication for transesophageal echocardiography (e.g. esophageal resection, higher-grade esophagus varices) and insufficient sonography conditions for transthoracic echocardiography
• terminal kidney disease with dialysis
• Sepsis/septic shock ≤ 8 months
• pregnancy/breastfeeding
• therapy limitation, DNR / DNI order
• life expectancy ≤ 6 months due to comorbidities
• previous participation in this study
• participation in another intervention study

Arm 2
• Sepsis/septic shock ≤ 8 months
• infection at point of inclusion
• acute organ failure (except cardiac decompensation/cardiogenic shock due to dilated cardiomyopathy) ≤ 6 months
• cardiopulmonary resuscitation<4 weeks
• complex structural congenital heart condition (TGA, Tetralogy of Fallot, endocardial cushion defect etc.)
• hemodynamic relevant shunt deficit
• cardiogenic shock (INTERMACS 1) at point of inclusion
• heart transplantation in medical history
• mechanical heart supporting system
• pneumonectomy in medical history
• liver cirrhosis Child C
• terminal kidney disease with dialysis
• insufficient sonographic conditions for transthoracic echocardiography
• pregnancy/breastfeeding
• therapy limitation / DNR / DNI order
• life expectancy ≤ 6 months due to comorbidities
• previous participation in this study
• participation in another intervention study

Arm 3
• sepsis/septic shock ≤ 8 months
• infection at point of inclusion
• ICU treatment ≤ 6 months
• cardiopulmonary resuscitation<4 weeks
• heart surgery (including heart transplantation) in medical history
• significant pre-existing cardiac condition
o higher-degree valvular heart disease
(grade 3 valve disease, symptomatic aortic stenosis, medium-degree mitral valve insufficiency with reduced ejection fraction or clinical symptoms)
o complex structural congenital heart condition (TGA, Tetralogy of Fallot, endocardial cushion defect etc.)
o hemodynamic relevant shunt deficit
o cardiomyopathy
o pre-existing significantly reduced cardiac performance
(ejection fraction < 45 % or 10 % below norm value)
o pre-existing pulmonary hypertension
o myocardial infarction ≤ 1 year in medical history
• pneumonectomy in medical history
• liver cirrhosis Child C
• terminal kidney disease with dialysis
• insufficient sonography conditions for transthoracic echocardiography
• pregnancy/breastfeeding
• life expectancy ≤ 6 months due to comorbidities
• previous participation in this study
• participation in another intervention study

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Addresses

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    • NWG Translational Septomics, Zentrum für Innovationskomepetenz (ZIK) Septomics, Universitätklinikum Jena
    • Ms.  Dr. Dr. med.  Sina  Coldewey 
    • Am Klinikum 01
    • 07747  Jena
    • Germany
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    • NWG Translational Septomics, Zentrum für Innovationskompetenz (ZIK) Septomics, Universitätsklinikum Jena
    • Ms.  Dr. Dr. med.  Sina  Coldewey 
    • Am Klinikum 1
    • 07747  Jena
    • Germany
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    • NWG Translational Septomics, ZIK Septomics, Universitätsklinikum Jena
    • Mr.  Dr.   Charles   Neu 
    • Am Klinikum 1
    • 07747  Jena
    • Germany
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Sources of Monetary or Material Support

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    • NWG Translational Septomics gefördert durch Bundesministerium für Bildung und Forschung (BMBF)
    • 10115  Berlin
    • Germany
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Status

  •   Recruiting ongoing
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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.