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

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock

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.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow - Klinikum, Charité- Universitätsmedizin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Critically ill patients with septic shock

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Critically ill patients; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nagalase enzyme activity	Nagalase Enzyme activity is expressed in nmol/min per Milliliter. Analysis is evaluated with the perioperative Nagalase results of 10 patients in the clinical trial Phydelio (EudraCT-No 2008-007237-47).	This parameter is measured at the beginning of the investigation
Venous return	Venous return will be assessed after ICU admission by venous return pressure gradient (dVR)	This parameter is measured at the beginning of the investigation

Collaborators and Investigators

• Sponsor: Claudia Spies

Publications and helpful links

General Publications

• Bellet MM, Deriu E, Liu JZ, Grimaldi B, Blaschitz C, Zeller M, Edwards RA, Sahar S, Dandekar S, Baldi P, George MD, Raffatellu M, Sassone-Corsi P. Circadian clock regulates the host response to Salmonella. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9897-902. doi: 10.1073/pnas.1120636110. Epub 2013 May 28.
• Lim AS, Chang AM, Shulman JM, Raj T, Chibnik LB, Cain SW, Rothamel K, Benoist C, Myers AJ, Czeisler CA, Buchman AS, Bennett DA, Duffy JF, Saper CB, De Jager PL. A common polymorphism near PER1 and the timing of human behavioral rhythms. Ann Neurol. 2012 Sep;72(3):324-34. doi: 10.1002/ana.23636.
• Lachmann G, Ananthasubramaniam B, Wunsch VA, Scherfig LM, von Haefen C, Knaak C, Edel A, Ehlen L, Koller B, Goldmann A, Herzel H, Kramer A, Spies C. Circadian rhythms in septic shock patients. Ann Intensive Care. 2021 Apr 26;11(1):64. doi: 10.1186/s13613-021-00833-5.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): January 21, 2018
• Study Completion (Actual): March 31, 2019

Study Registration Dates

• First Submitted: January 20, 2014
• First Submitted That Met QC Criteria: January 22, 2014
• First Posted (Estimate): January 24, 2014

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 12, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Clock genes, circadian regulation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: SeptiClock