Critical IllnessCIRCLESNCT05795881
Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness
A study testing Cyclic daytime enteral nutrition in people with Critical Illness and Intensive Care Unit, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
Disruption of circadian rhythms is frequently observed in patients in the intensive care unit (ICU) and is associated with worse clinical outcomes. The ICU environment presents weak and conflicting timing cues to the circadian clock, including continuous enteral nutrition. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness, Intensive Care Unit, Circadian Rhythm
- What is being tested?
- Cyclic daytime enteral nutrition
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteNetherlands
- Study dates
- 14 Jun 2023to 15 Mar 2025
- Phase
- Interventional
- 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
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years old
- Receiving of or intention to start enteral nutrition via nasogastric or nasoduodenal tube
- Arterial line
- Expected duration of ICU admission > 48 hours
Who cannot join
- Receiving parenteral nutrition
- Prior night-time (20.00h - 8.00h) enteral tube feeding within the same hospitalization before study inclusion
- Readmission to ICU with prior study inclusion
- Chronic enteral tube feeding prior to current admission
- Presence of one or more contraindications of enteral feeding and/or at significant risk for gastrointestinal tolerance according to standard protocol (including but not limited to gastrointestinal haemorrhage, intestinal ischemia or necrosis, impaired digestive tract integrity due to obstruction or perforation, gastrectomy, enterectomy, history of gastroparesis or oesophageal dysmotility or expected surgery within 24 hours)
- Patients with glycaemic emergency (including but not limited to hyperglycaemic hyperosmolar nonketotic coma, diabetic ketoacidosis, severe hypoglycaemia resulting in ICU admission) or patients controlling their glucose levels and insulin dosing via continuous glucose monitoring
Show all 11Show fewer
- Expected death within 24 hours
- Do-not-resuscitate (DNR) order
- Treatment with extracorporeal membrane oxygenation
- Severe neurological damage (significant neurological abnormalities such as bleeding, ischemia, neurotrauma or severe encephalopathy with Glasgow Coma Scale ≤ 8)
- Suspected or confirmed pregnancy
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness: CIRCLES Study
Disruption of circadian rhythms is frequently observed in patients in the intensive care unit (ICU) and is associated with worse clinical outcomes. The ICU environment presents weak and conflicting timing cues to the circadian clock, including continuous enteral nutrition. The goal of this clinical trial is to evaluate the effect of timing of enteral nutrition on the circadian rhythm in critically ill patients. Patients admitted to the intensive care unit will be allocated to receive either continuous or cyclic daytime (8am to 8 pm) enteral feeding. Differences in circadian rhythms will be assessed by 24h patterns in core body temperature, heart rate variability, melatonin and peripheral clock gene expression. Secondary outcomes include depth of sleep, glucose variability and incidence of feeding intolerance. This study is expected to contribute to the optimalisation of circadian rhythms in the ICU.
- Being tested
- Cyclic daytime enteral nutrition
- Keywords
- Randomized Controlled Trial
- Medical subject headings
- Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cyclic daytime enteral nutritionOther
The allocated feeding schedule is followed from the start of enteral nutrition after ICU admission until discharge from the ICU.
| Study group | Role | What they receive |
|---|---|---|
| Control group | No intervention | continuous enteral nutrition: 24 hours a day (standard of care) |
| Intervention group | Experimental | cyclic daytime enteral nutrition: between 8 a.m. and 8 p.m. (same amount of nutrition as control group) Receives: Other: Cyclic daytime enteral nutrition |
What is being measured
The primary outcome is the main question the study is designed to answer.
Amplitude of 24-h rhythm of core body temperature
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase 24-h rhythm of core body temperature
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Secondary outcomes (18)
Amplitude of 24-h rhythm of plasma melatonin levels
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm of plasma melatonin levels
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate variability
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate variability
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in systolic blood pressure
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in systolic blood pressure
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate
Determined by cosinor analysis
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Peripheral clock gene expression
Time of day-dependent difference in clock gene expression in PBMCs isolated from blood samples collected at 12 p.m. and 12 a.m.
Measured: Day 3 (12 p.m.) to day 4 (12 a.m.) after start of the study intervention (= start of enteral nutrition)
Depth of sleep
Daytime (8 a.m. to 8 p.m.) to nighttime (8 p.m. to 8 a.m.) ratio of gamma to delta spectral power ratio in EEG measured with a sleep headband
Measured: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Mean daily rate of hyperglycaemia/hypoglycaemia
Hypoglycaemia is defined as glucose levels < 3.5 mmol/L, hyperglycaemia is defined as glucose levels >10 mmol/L
Measured: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily glucose variability
Mean of standard deviation of glucose levels per day
Measured: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily insulin administration
Mean of number of insulin units used per day
Measured: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily caloric intake
Mean of percentage of recommended calories that patient receives per day of interest during study period
Measured: From start of study intervention (enteral nutrition) to end of study intervention
Daily rates of gastric retention
Gastric retention is defined as gastric residual volume > 200 mL
Measured: From start of study intervention (enteral nutrition) to end of study intervention
28-day mortality
28-day mortality
Measured: Up to 28 days
Days on mechanical ventilation
Days on mechanical ventilation
Measured: From ICU admission to ICU discharge
ICU length of stay
ICU length of stay
Measured: From ICU admission to ICU discharge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2023
- Study start14 Jun 2023
- Primary completion15 Mar 2025
- Study completion15 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Critical IllnessStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Investigator-Initiated Randomized Controlled Trial
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, David van westerloo, Leiden University Medical Center
- Investigators
- David J van Westerloo, PhD, MD, Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05795881
- Sponsor's protocol ID
- P22.080
- Acronym
- CIRCLES
- Status last verified
- Mar 2025
- First submitted
- 6 Mar 2023
- Last updated
- 20 Mar 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Immediately following publication, the individual participant data that underlie the results reported in the published article will be shared after deidentificiation. The data will be shared upon request with researchers who wish to access the data for any purpose.
Publications
Kouw IWK, Heilbronn LK, van Zanten ARH. Intermittent feeding and circadian rhythm in critical illness. Curr Opin Crit Care. 2022 Aug 1;28(4):381-388. doi: 10.1097/MCC.0000000000000960. Epub 2022 Jul 5.
PubMed 35797531Hiemstra FW, van Gent MF, de Jonge E, van Westerloo DJ, Kervezee L. Effect of cyclic daytime versus continuous enteral nutrition on circadian rhythms in critical illness (CIRCLES): Study protocol for a randomized controlled trial. Contemp Clin Trials. 2025 Jul;154:107927. doi: 10.1016/j.cct.2025.107927. Epub 2025 Apr 27.
PubMed 40300711Luetz A, Spies C, Kervezee L. It's about time: circadian medicine in the intensive care unit. Intensive Care Med. 2024 Feb;50(2):283-286. doi: 10.1007/s00134-023-07297-0. Epub 2023 Dec 19. No abstract available.
PubMed 38112772
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness: CIRCLES Study
- ClinicalTrials.gov ID
- NCT05795881
- Acronym / sponsor ID
- CIRCLES / P22.080
- Keywords
- Randomized Controlled Trial
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- 14 Jun 2023 (actual)
- Primary completion
- 15 Mar 2025 (actual)
- Study completion
- 15 Mar 2025 (actual)
- First posted
- 3 Apr 2023 (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.
Disruption of circadian rhythms is frequently observed in patients in the intensive care unit (ICU) and is associated with worse clinical outcomes. The ICU environment presents weak and conflicting timing cues to the circadian clock, including continuous enteral nutrition. The goal of this clinical trial is to evaluate the effect of timing of enteral nutrition on the circadian rhythm in critically ill patients. Patients admitted to the intensive care unit will be allocated to receive either continuous or cyclic daytime (8am to 8 pm) enteral feeding. Differences in circadian rhythms will be assessed by 24h patterns in core body temperature, heart rate variability, melatonin and peripheral clock gene expression. Secondary outcomes include depth of sleep, glucose variability and incidence of feeding intolerance. This study is expected to contribute to the optimalisation of circadian rhythms in the ICU.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Investigator-Initiated Randomized Controlled Trial
| Arm | Type | Receives |
|---|---|---|
| Control group | No intervention | –continuous enteral nutrition: 24 hours a day (standard of care) |
| Intervention group | Experimental | Other: Cyclic daytime enteral nutritioncyclic daytime enteral nutrition: between 8 a.m. and 8 p.m. (same amount of nutrition as control group) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age ≥ 18 years old
- Receiving of or intention to start enteral nutrition via nasogastric or nasoduodenal tube
- Arterial line
- Expected duration of ICU admission > 48 hours
Key exclusion criteria (11 listed)
- Receiving parenteral nutrition
- Prior night-time (20.00h - 8.00h) enteral tube feeding within the same hospitalization before study inclusion
- Readmission to ICU with prior study inclusion
- Chronic enteral tube feeding prior to current admission
- Presence of one or more contraindications of enteral feeding and/or at significant risk for gastrointestinal tolerance according to standard protocol (including but not limited to gastrointestinal haemorrhage, intestinal ischemia or necrosis, impaired digestive tract integrity due to obstruction or perforation, gastrectomy, enterectomy, history of gastroparesis or oesophageal dysmotility or expected surgery within 24 hours)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cyclic daytime enteral nutritionThe allocated feeding schedule is followed from the start of enteral nutrition after ICU admission until discharge from the ICU. | Other | Intervention group |
Primary outcome
Amplitude of 24-h rhythm of core body temperature
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Determined by cosinor analysis
Acrophase 24-h rhythm of core body temperature
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Determined by cosinor analysis
18 secondary outcomes
Amplitude of 24-h rhythm of plasma melatonin levels
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm of plasma melatonin levels
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate variability
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate variability
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in systolic blood pressure
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in systolic blood pressure
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Amplitude of 24-h rhythm in heart rate
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Acrophase of 24-h rhythm in heart rate
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Peripheral clock gene expression
Time frame: Day 3 (12 p.m.) to day 4 (12 a.m.) after start of the study intervention (= start of enteral nutrition)
Depth of sleep
Time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)
Mean daily rate of hyperglycaemia/hypoglycaemia
Time frame: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily glucose variability
Time frame: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily insulin administration
Time frame: From start of study intervention (enteral nutrition) to end of study intervention
Mean daily caloric intake
Time frame: From start of study intervention (enteral nutrition) to end of study intervention
Daily rates of gastric retention
Time frame: From start of study intervention (enteral nutrition) to end of study intervention
28-day mortality
Time frame: Up to 28 days
Days on mechanical ventilation
Time frame: From ICU admission to ICU discharge
ICU length of stay
Time frame: From ICU admission to ICU discharge
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2025.
- Background: PubMed 35797531Kouw IWK, Heilbronn LK, van Zanten ARH. Intermittent feeding and circadian rhythm in critical illness. Curr Opin Crit Care. 2022 Aug 1;28(4):381-388. doi: 10.1097/MCC.0000000000000960. Epub 2022 Jul 5.
- Derived from this study: PubMed 40300711Hiemstra FW, van Gent MF, de Jonge E, van Westerloo DJ, Kervezee L. Effect of cyclic daytime versus continuous enteral nutrition on circadian rhythms in critical illness (CIRCLES): Study protocol for a randomized controlled trial. Contemp Clin Trials. 2025 Jul;154:107927. doi: 10.1016/j.cct.2025.107927. Epub 2025 Apr 27.
- Derived from this study: PubMed 38112772Luetz A, Spies C, Kervezee L. It's about time: circadian medicine in the intensive care unit. Intensive Care Med. 2024 Feb;50(2):283-286. doi: 10.1007/s00134-023-07297-0. Epub 2023 Dec 19. No abstract available.
- Individual participant dataSharing planned: Yes. Immediately following publication, the individual participant data that underlie the results reported in the published article will be shared after deidentificiation. The data will be shared upon request with researchers who wish to access the data for any purpose.
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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.
David J van Westerloo, PhD, MD principal investigator
Leiden University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cyclic daytime enteral nutrition in people with Critical Illness and Intensive Care Unit, run by Leiden University Medical Center at 1 site in Netherlands.
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 4 inclusion and 11 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: finished, as of the sponsor's last update on 20 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Amplitude of 24-h rhythm of core body temperature (time frame: Day 3 (8 a.m.) to day 4 (8 a.m.) after start of the study intervention (= start of enteral nutrition)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05795881, which also lists 3 linked publications.
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 20 Mar 2025.