Circadian Rhythm DisordersNCT04063332
Functionality of Endogenous Biological Clock in Sepsis
An observational study of Circadian Rhythm Disorders and Sepsis, run by University of Athens at 2 sites in Greece.
Trial summary
The aim of the current study is to demonstrate dysregulation of immune system΄s circadian rhythms as a consequence of sepsis, as well as marked malfunction of the central circadian clock in comparison with patients without sepsis , the presence of which burdens independently the final outcome and , hence, need to be… Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Circadian Rhythm Disorders, Sepsis
- How many people
- 60 participants
- Where
- 2 sitesGreece
- Study dates
- 3 Jun 2019to Jun 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: * GROUP A: absolutely healthy individuals without any comorbidities, working at the same environment with the rest of groups (doctors are excluded as belong to one of the special categories) patients with sepsis as defined by the Sepsis-3 classification criteria3 * GROUP Β: control patients without sepsis or infection and with the same exactly comorbidities (ideally ≤2 suffering organ systems) , i.e. identical Charlson score, identical mental status and age difference ≤ 5 years with group A * GROUP C: patients with sepsis as defined by the Sepsis-3 classification criteria3
Who may be able to join
- Adults (age ≥18 years)
- Written informed consent
- Male or female gender
- Οne of the following cases:
- Healthy controls without comorbidities OR
- Patients without sepsis or infection , with identical Charlson Comorbidity Index and same mental status with the septic patients OR
- Patients with sepsis
Who cannot join
- Failure to obtain written informed consent
- Age <18 years
- Pregnancy or breastfeeding
- Solid tumor or hematologic malignancy
- Asthma
- Neurodegenerative disease
Show all 12Show fewer
- Traumatic brain injury
- Confirmed depression
- Autoimmune disorders
- Special categories following unfixed or varying routine schedules (e.g. travels overseas or even short distances, if frequent/jet lag/on-call duties/nightshifts with regard to doctors,security guards,singers)
- Per os or iv corticosteroids daily intake of dose at least
- Corticosteroid oral or intravenous intake of at least 0.4 mg/kg of equivalent prednisone daily over the last 15 days
Trial locations and contacts
2 sites in 1 country.
Greece2 sites, 2 recruiting
- Recruiting
2nd Department of Intensive Care Medicine, Attikon University Hospital
Athens, Attica, 12462
Apostolos Armaganidis, MD, PhD, 0030 210 5832183, aarmag@med.uoa.gr
- Recruiting
4th Department of Internal Medicine, Attikon University Hospital
Athens, Attica, 12462
Evangelos J Giamarellos-Bourboulis, MD, PhD, +302107480662, egiamarel@med.uoa.gr
Maria G Kalogridi, MD, +302105831916
About this study
The aim of the current study is to demonstrate dysregulation of immune system΄s circadian rhythms as a consequence of sepsis, as well as marked malfunction of the central circadian clock in comparison with patients without sepsis , the presence of which burdens independently the final outcome and , hence, need to be addressed.
Read the detailed description
Sepsis is number one cause of death within the critically ill patients ,with mortality that reaches a rate of 70%,while in case of the establishment of septic shock and multi organ failure it can rise up to 80%.Septic shock is the most common cause of death in the ICUs. It has been estimated that 25% of the total of septic patients will develop severe sepsis (sepsis and organ failure), while septic shock (sepsis and cardiovascular failure).
In order to call a biological rhythm circadian, the following 3 criteria must be satisfied:
- Insistence on stable conditions, with endogenous period of about 24 hours.
- Independence of ambient temperature, so that almost always progresses at the same rate (same frequency), independent of temperature.
- This endogenous rhythm, of approximately 24 hours, can be synchronized in exactly 24 hours, influenced by environmental factors, such as light/dark cycles, social interactions, etc.
Many organic systems follow a circadian pattern, among others the immune system,on the grounds that peripheral blood lymphocytes own all the forementioned genes, whose coordinated expression with that particular periodicity results in the generation of maximum (peak) and minimum (nadir) of the number of circulating cells, their activity, the production and secretion of cytokines etc.This endogenous attitude is lost in case of sepsis, due to few or absent stimuli deriving from the central clock. As a result, an additional compounding factor comes up in the immune system ,which fails to fight the infectious agent and that inefficient immune response aggravates the circadian desynchronization , creating a vicious circle.
The direct evaluation of circadian rhythms' entails the examination of suprachiasmatic neurons' functionality, through biopsies from the examined patients ,which constitutes an ethically questionable ,practically expensive, time-consuming and quite demanding procedure. Thus, the estimation of actual circadian profile will take place indirectly, driven by a series of biomarkers, indicative of the functional status of the ''central biological clock'' found at the suprachiasmatic nucleus of CNS (melatonin, cortisol, core body temperature),as well as the ''peripheral clock'' placed at the immune system cells (Clock/ Bmal1 , Per/Cry genes' expression).
The purpose of this prospective, observational, case-control study is to investigate the discrepancy in levels of circadian biomarkers in patients suffering from sepsis in comparison with those coming from other ,non-septic patients in the same environment as well as deviation from healthy controls' values, and secondarily to assess the effect of septic syndrome in later development of endogenous clock that regulates daily life with regard to the quality of life that follows recovery.
- Conditions
- Circadian Rhythm Disorders, Sepsis
- Keywords
- circadian, sepsis, clock, melatonin
- Medical subject headings
- Chronobiology Disorders, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| GROUP A | Absolutely healthy individuals without any comorbidities, working at the same environment with the rest of groups (doctors are excluded as belong to one of the special categories) patients with sepsis as defined by the Sepsis-3 classification criteria3 | |
| GROUP B | Control patients without sepsis or infection and with the same exactly comorbidities (ideally ≤2 suffering organ systems) , i.e. identical Charlson score, identical mental status and age difference ≤ 5 years with group A | |
| GROUP C | Patients with sepsis as defined by the Sepsis-3 classification criteria3 |
What is being measured
The primary outcome is the main question the study is designed to answer.
The substantial discrepancy in the values of melatonin, cortisol and core body temperature (central CLOCK circadian markers) between septic and non-septic patients.
Different values in melatonin,cortisol, core body temperature .
Measured: 7 days
The substantial discrepancy in the circadian rhythms' genes expression levels (peripheral clock markers) between septic and non-septic patients ,within their peripheral blood leucocytes .
Different mRNA levels of clock, bmal1, per, cry genes within peripheral blood leucocytes.
Measured: 7 days
The difference in the extent of deviation from normal, with regard to the values of melatonin-cortisol-core body temperature (circadian triad) between septic and non-septic patients.
Extent of abnormality in the values of melatonin,cortisol and core body temperature .
Measured: 7 days
The difference in the extent of deviation from normal, with regard to the levels of circadian rhythms' genes expression (immune system's clock) between septic and non-septic patients ,within their peripheral blood leucocytes .
Extent of abnormality in the mRNA levels of clock, bmal1, per, cry genes within peripheral blood leucocytes.
Measured: 7 days
Secondary outcomes (6)
Mortality rate at 28 days.
Differences in early (28-day) all-cause mortality rate between septic and matched non-septic patients .
Measured: 28 days
Mortality rate at 90 days.
Differences in middle term (90-day) all-cause mortality rate between septic and matched non-septic patients.
Measured: 90 days
Munich ChronoType Questionnaire results ,including Mid-sleep, Sleep Duration on both work and free days (MSw, MSf, MSfsc, SLDw, SLDf, SLDØ, chronotype).
Rate of circadian physiology restoration, concerning the discharged subgroup which is recovering from sepsis, with regard to daily routine and quality of life.
Measured: 30 days
Pittsburgh Sleep Quality Index (Global PSQI Score).
Sum (range 0 to 21) of seven components,each scored 0 (no difficulty) to 3 (severe difficulty).These entail Subjective sleep quality, Sleep latency, duration, efficiency and disturbance, in addition to Use of sleep medication and Daytime dysfunction.
Measured: 30 days
Munich ChronoType Questionnaire results ,including Mid-sleep, Sleep Duration on both work and free days (MSw, MSf, MSfsc, SLDw, SLDf, SLDØ, chronotype).
Rate of circadian physiology restoration ,concerning the discharged subgroup which is recovering from sepsis, with regard to daily routine and quality of life.
Measured: 60 days
Pittsburgh Sleep Quality Index (Global PSQI Score).
Sum (range 0 to 21) of seven components,each scored 0 (no difficulty) to 3 (severe difficulty).These entail Subjective sleep quality, Sleep latency, duration, efficiency and disturbance, in addition to Use of sleep medication and Daytime dysfunction.
Measured: 60 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2019
- Study start3 Jun 2019
- Primary completionJun 2024 (estimated)
- Study completionJun 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Circadian Rhythm DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Athens
- Sponsor type
- University, hospital or other
- Collaborators
- Hellenic Sepsis Study Group
- Responsible party
- Principal investigator, Evangelos J. Giamarellos-Bourboulis, M.D., University of Athens
- Investigators
- Evangelos J Giamarellos-Bourboulis, MD, PhD, Principal investigator, University of Athens
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04063332
- Sponsor's protocol ID
- CLOCK
- Status last verified
- Dec 2023
- First submitted
- 13 Aug 2019
- Last updated
- 12 Dec 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Functionality of Endogenous Biological Clock in Sepsis
- ClinicalTrials.gov ID
- NCT04063332
- Acronym / sponsor ID
- CLOCK
- Conditions
- Circadian Rhythm Disorders, Sepsis
- Keywords
- circadian, sepsis, clock, melatonin
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of AthensUniversity, hospital or other
- Collaborators
- Hellenic Sepsis Study Group
- Study start
- 3 Jun 2019 (actual)
- Primary completion
- Jun 2024 (estimated)
- Study completion
- Jun 2024 (estimated)
- First posted
- 21 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the current study is to demonstrate dysregulation of immune system΄s circadian rhythms as a consequence of sepsis, as well as marked malfunction of the central circadian clock in comparison with patients without sepsis , the presence of which burdens independently the final outcome and , hence, need to be addressed.
Detailed description
Sepsis is number one cause of death within the critically ill patients ,with mortality that reaches a rate of 70%,while in case of the establishment of septic shock and multi organ failure it can rise up to 80%.Septic shock is the most common cause of death in the ICUs. It has been estimated that 25% of the total of septic patients will develop severe sepsis (sepsis and organ failure), while septic shock (sepsis and cardiovascular failure).
In order to call a biological rhythm circadian, the following 3 criteria must be satisfied:
- Insistence on stable conditions, with endogenous period of about 24 hours.
- Independence of ambient temperature, so that almost always progresses at the same rate (same frequency), independent of temperature.
- This endogenous rhythm, of approximately 24 hours, can be synchronized in exactly 24 hours, influenced by environmental factors, such as light/dark cycles, social interactions, etc.
Many organic systems follow a circadian pattern, among others the immune system,on the grounds that peripheral blood lymphocytes own all the forementioned genes, whose coordinated expression with that particular periodicity results in the generation of maximum (peak) and minimum (nadir) of the number of circulating cells, their activity, the production and secretion of cytokines etc.This endogenous attitude is lost in case of sepsis, due to few or absent stimuli deriving from the central clock. As a result, an additional compounding factor comes up in the immune system ,which fails to fight the infectious agent and that inefficient immune response aggravates the circadian desynchronization , creating a vicious circle.
The direct evaluation of circadian rhythms' entails the examination of suprachiasmatic neurons' functionality, through biopsies from the examined patients ,which constitutes an ethically questionable ,practically expensive, time-consuming and quite demanding procedure. Thus, the estimation of actual circadian profile will take place indirectly, driven by a series of biomarkers, indicative of the functional status of the ''central biological clock'' found at the suprachiasmatic nucleus of CNS (melatonin, cortisol, core body temperature),as well as the ''peripheral clock'' placed at the immune system cells (Clock/ Bmal1 , Per/Cry genes' expression).
The purpose of this prospective, observational, case-control study is to investigate the discrepancy in levels of circadian biomarkers in patients suffering from sepsis in comparison with those coming from other ,non-septic patients in the same environment as well as deviation from healthy controls' values, and secondarily to assess the effect of septic syndrome in later development of endogenous clock that regulates daily life with regard to the quality of life that follows recovery.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| GROUP A | – | –Absolutely healthy individuals without any comorbidities, working at the same environment with the rest of groups (doctors are excluded as belong to one of the special categories) patients with sepsis as defined by the Sepsis-3 classification criteria3 |
| GROUP B | – | –Control patients without sepsis or infection and with the same exactly comorbidities (ideally ≤2 suffering organ systems) , i.e. identical Charlson score, identical mental status and age difference ≤ 5 years with group A |
| GROUP C | – | –Patients with sepsis as defined by the Sepsis-3 classification criteria3 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- * GROUP A: absolutely healthy individuals without any comorbidities, working at the same environment with the rest of groups (doctors are excluded as belong to one of the special categories) patients with sepsis as defined by the Sepsis-3 classification criteria3 * GROUP Β: control patients without sepsis or infection and with the same exactly comorbidities (ideally ≤2 suffering organ systems) , i.e. identical Charlson score, identical mental status and age difference ≤ 5 years with group A * GROUP C: patients with sepsis as defined by the Sepsis-3 classification criteria3
Key inclusion criteria (7 listed)
- Adults (age ≥18 years)
- Written informed consent
- Male or female gender
- Οne of the following cases:
Key exclusion criteria (12 listed)
- Failure to obtain written informed consent
- Age <18 years
- Pregnancy or breastfeeding
- Solid tumor or hematologic malignancy
- Asthma
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
The substantial discrepancy in the values of melatonin, cortisol and core body temperature (central CLOCK circadian markers) between septic and non-septic patients.
Time frame: 7 days
Different values in melatonin,cortisol, core body temperature .
The substantial discrepancy in the circadian rhythms' genes expression levels (peripheral clock markers) between septic and non-septic patients ,within their peripheral blood leucocytes .
Time frame: 7 days
Different mRNA levels of clock, bmal1, per, cry genes within peripheral blood leucocytes.
The difference in the extent of deviation from normal, with regard to the values of melatonin-cortisol-core body temperature (circadian triad) between septic and non-septic patients.
Time frame: 7 days
Extent of abnormality in the values of melatonin,cortisol and core body temperature .
The difference in the extent of deviation from normal, with regard to the levels of circadian rhythms' genes expression (immune system's clock) between septic and non-septic patients ,within their peripheral blood leucocytes .
Time frame: 7 days
Extent of abnormality in the mRNA levels of clock, bmal1, per, cry genes within peripheral blood leucocytes.
6 secondary outcomes
Mortality rate at 28 days.
Time frame: 28 days
Mortality rate at 90 days.
Time frame: 90 days
Munich ChronoType Questionnaire results ,including Mid-sleep, Sleep Duration on both work and free days (MSw, MSf, MSfsc, SLDw, SLDf, SLDØ, chronotype).
Time frame: 30 days
Pittsburgh Sleep Quality Index (Global PSQI Score).
Time frame: 30 days
Munich ChronoType Questionnaire results ,including Mid-sleep, Sleep Duration on both work and free days (MSw, MSf, MSfsc, SLDw, SLDf, SLDØ, chronotype).
Time frame: 60 days
Pittsburgh Sleep Quality Index (Global PSQI Score).
Time frame: 60 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Evangelos J Giamarellos-Bourboulis, MD, PhD principal investigator
University of Athens
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Circadian Rhythm Disorders and Sepsis, run by University of Athens at 2 sites in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Evangelos J Giamarellos-Bourboulis, MD, PhD (+302107480662, egiamarel@med.uoa.gr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The substantial discrepancy in the values of melatonin, cortisol and core body temperature (central CLOCK circadian markers) between septic and non-septic patients. (time frame: 7 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2023.