Clock Genes in Patients With Refractory Septic Shock (SeptiClock) - Pilot Study

Study Overview
=================
Brief Summary
-----------------
Despite large efforts trying to improve diagnostic and therapy of sepsis have been made over the last decade (e.g. initiation of the Surviving Sepsis Campaign, defining evidence based sepsis therapy bundles) the mortality of septic shock remains high and causes high socioeconomical burden of disease. The purpose of this pilot study is to evaluate the design and conduct of a projected full scale clinical trial.

Detailed Description
-----------------
A functional clock is required for induction of several proinflammatory genes, not shown in septic patient settings, yet. Clock genes are involved in modulating the activity of several transcription factors that are important regulators of immune functions (e.g. HIF1-α, STAT1, STAT3, and NF-κB) (Bellet MM et al., 2013). Furthermore, polymorphisms such as rs7221412, a common polymorphism near period homolog 1 (PER1), was associated with the timing of activity rhythms and also showed a suggestive time-dependent relationship with both cerebral cortex and monocytes PER1 expression and an association with time of death (Lim ASP et al., 2012). This explorative project is a pilot study. First data are generated for the assessment of the circadian system in patients with septic shock.

Official Title
-----------------
Clock Genes in Patients With Refractory Septic Shock (SeptiClock) - Pilot Study

Conditions
-----------------
Septic Shock

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients with age 18 years and above, Patient at intensive care units (8i, 9i and 1i at Charité - University Medicine Berlin , Campus Virchow- Klinikum), Septic shock (ACCP/SCCM (American College of Chest Physicians/Society of Critical Care Medicine) consensus definitions) AND Norepinephrine dosage of >0.3 μg/kg/min for at least 2 hours Exclusion Criteria: Pregnant or lactating female patient, Participation in another interventional study (30 days before study inclusion and during study participation), Acute leucemia, Severe leukocytosis (>50,000/nl), Severe thrombocytopenia (<5,000/nl), Autoimmune disease with systemic medication of ≥10 mg prednisolone equivalent or previous transplantation, Patients receiving interferon therapy (last 14 days), Patients with known hypersensitivity GM-CSF or known antibodies against GM-CSF, yeast-derived products or any component of the study medication, Ongoing (concomitant) chemotherapy or radiotherapy for malignancy, Acute pulmonary embolism or acute myocardial infarction within last 72 hours, Cardiopulmonary resuscitation within last 7 days, Moribund patient (life expectancy <72 hrs.), Presence of a do-not-resuscitate or do-not-intubate order, Known human immunodeficiency virus (HIV) infection or chronic viral hepatitis Lacking willingness to save and hand out data within the study Accommodation in an institution due to an official or judicial order The informed consent of the patient or the subject's legally acceptable representative can´t be obtained in time Patient has a power of attorney or patient's provision, where he/she refuses participation in any clinical trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Critically ill patients<br>Intensive care unit patients with refractory septic shock | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of circadian regulation | Circadian regulation by expression of clock genes | These parameters are measured during intensive care unit stay, for a maximum of 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time on mechanical ventilation |  | They are followed up until the end of intensive care unit stay - or, for a maximum of 28 days | 
| Intensive care unit length of stay |  | Participants will be followed for the duration of intensive care stay, an expected average of 4 weeks | 
| Hospital length of stay |  | Participants will be followed for the duration of intensive care stay, an expected average of 5 weeks | 
| Simplified Acute Physiology Score (SOFA II) |  | They are measured until the end of intensive care unit stay - or, for a maximum of 28 days. | 
| Sequential Organ Failure Assessment (SOFA) |  | They are measured until the end of intensive care unit stay - or, for a maximum of 28 days. | 
| Therapeutic Intervention Scoring System (TISS-28) |  | They are measured until the end of intensive care unit stay - or, for a maximum of 28 days. | 
| Mortality |  | 6 months after intensive care unit discharge | 
| Light frequencies |  | Light frequencies are measured until the end of intensive care unit stay - or, for a maximum of 28 days | 
| Light levels (lux) |  | Light levels are measured until the end of intensive care unit stay - or, for a maximum of 28 days | 
| Cortisol |  | This parameter is measured in ng/ml during intensive care unit stay, for a maximum of 3 days | 
| Melatonin |  | This parameter is measured in pg/ml during intensive care unit stay, for a maximum of 3 days | 
| Quality of life | Quality of life is measured by SF-36 questionnaire | Up to 3 and 6 months | 
| Cognitive function | Cognitive function is measured by Repeatable Battery for the Assessment of Neuropsychological Status | Up to 3 and 6 months | 
| Multiplex-Genexpression analysis | Ncounter neuroinflammation and micro rna panel are analysed | These parameters are measured during intensive care unit stay, for a maximum of 3 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Clock genes, circadian regulation