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NCT Number: NCT06245434

Circadian Rhythmicity During Coma Awakening

Acute brain injury is a major cause of admission to intensive care units, as well as of mortality and morbidity, worldwide and for all age groups. With most patients surviving these injuries thanks to recent medical advances, society is facing not only the growing burden of disability, but above all the ethical issues involved in withdrawal of life-sustaining therapies (WSLT). To resolve this dilemma, effective treatment would be necessary, but this is hampered by our limited knowledge of the pathophysiological mechanisms of the natural history of coma, from onset to recovery. A more systematic description of coma awakening using a multimodal battery in intensive care unit patients would enable us to refine the awakening and re-emergence of consciousness and define appropriate biomarkers for selecting candidates in interventional studies.

The investigators hypothesize that the current postulate of successive stages (i.e. from one clinical class to the next) of coma recovery is incomplete, as it does not take into account the rhythmic nature of wakefulness. The investigators propose that the best correlate of the natural history of coma recovery is a gradual shift from the loss of physiological cycles to a circadian rhythmicity of arousal indices (behavioural and neurophysiological) and a wide amplitude of metric fluctuations in assessing content richness.

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Key information

Age range

17 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Service de Réanimation Polyvalente Neurologique Hôpital Neurologique Pierre Wertheimer

Bron, Lyon, 69500, France

Location status: Recruiting

Location contact

FLORENT, GOBERT, M.D. Ph.D.

CONTACT

[email protected]

0472681296 ext. +33

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Group 1

  • Admission to the Neurological Intensive Care Unit
  • Initial disorder of consciousness (GCS < 8) or initial brain lesion (on CT or MRI) requiring intubation and sedation during management (for upper airway protection or due to coma)
  • Intubated patient under mechanical ventilation with no response to simple commands
  • Weaning from sedation : acquired / possible within 7 days of inclusion in the absence of new complications
  • Severity of clinical or morphological impairment leading to risk of persistent disturbance of consciousness
  • Sedation discontinued or able to be discontinued within 3 month of initial management of the disorder of consciousness or brain injury
  • Effective treatment of the cause of admission without risk of short-term recurrence
  • Patient aged 17 or over
  • Urinary catheter in place at the time of inclusion and to remain in place until Visit N°1
  • Presence of relatives able to sign consent or of the minor's legal representative

Group 2

  • Admission to the Neurological Intensive Care Unit or the Neurological Continuing Care Unit
  • Absence of severe disorder of consciousness but possibility of minimal alteration of the initial Glasgow score (GCS between 9 and 15) with no time limit, with a stratification of three consecutive patient populations distinguished by the initial neurological alteration:
  • GCS = 15
  • GCS < 15 by predominance of an initial defect in responses to simple or complex commands obtained by motor or verbal means, without abnormality of arousal (E score = 4 but M score < 6 and/or V score < 5)
  • GCS < 15 with predominant initial somnolence, with or without abnormal motor or verbal responses to simple or complex commands (E score = 2 or 3 but M score = 6 and/or V score = 5).
  • Existence of functional communication or functional use of objects at inclusion
  • Mechanism of injury for which the aetiology is no longer active or at risk of recurrence
  • Patient aged 17 or over
  • Urinary catheter in place at the time of inclusion and to remain in place until Visit N°1
  • In the case of impaired judgement despite functional communication or in the case of aphasia with functional use of objects: presence of relatives able to sign consent or of the legal representative of the minor or of the legal representative of the protected adult.

Group 3

  • Admission to the Adult Post-Resuscitation Rehabilitation Department, in the Neurological Multidisciplinary Intensive Care Unit
  • Disturbance of consciousness defined by an absence of communication or an absence of functional use of objects (for patients with aphasia), i.e. the two signs that could indicate emergence from the pauci-relational state, which includes patients presenting :
  • persistent coma
  • a vegetative state (or unresponsive wakefulness syndrome)
  • a pauci-relational state (MCS- or MCS+ if responding to simple commands).
  • Persistent within the following timeframe
  • More than 3 months after the initial management of the disorder of consciousness or brain injury
  • More than 1 month after a post-anoxic coma.
  • Mechanism of injury for which the aetiology is no longer active or at risk of recurrence
  • Patient aged 17 or over
  • Presence of relatives likely to sign the consent or of the legal representative of a minor or of the legal representative of a protected adult

Exclusion criteria

Group 1

  • Subjects with a contraindication to MRI scans
  • Admission for status epilepticus
  • Existence of status epilepticus during the stay and persisting for > 24h or presenting an electrical remission for less than 48h prior to inclusion
  • Post-anoxic coma with bilateral abolition of N20 PES cortical responses
  • Coma related to a potentially recurrent cause of coma (tumours, infectious diseases with risk of relapse and inflammatory diseases)
  • Moribund patient (life expectancy < 24h) or in WLST (no assessment possible of the dynamics of ongoing awakening)
  • Haemodynamic or respiratory instability incompatible with a prolonged attempt to stop sedation (except in the case of scheduled surgery outside the visit dates)
  • Patients under guardianship, curatorship or safeguard of justice
  • Patients not affiliated to the French health insurance system
  • Pregnant women or women of childbearing age without proof of the absence of a current pregnancy

Group 2

  • Subjects with a contraindication to MRI scans
  • Epileptic seizures on admission or during the stay
  • Single seizure: if no rapid return to consciousness (GCS < 8 for > 12 hours)
  • > 2 distinct epileptic seizures regardless of the duration of loss of consciousness
  • Status epilepticus
  • Post-anoxic coma with bilateral abolition of N20 cortical PES responses.
  • Coma linked to a potentially recurrent cause of coma (tumour, infection with risk of relapse and inflammation).
  • A moribund patient (life expectancy < 24 hours) or a patient undergoing WLST with a high risk of death before the end of the study (inclusion possible if no therapeutic escalation is decided in a stabilised patient).
  • Haemodynamic or respiratory instability incompatible with prolonged evaluation of the absence of sedation (risk of general anaesthesia for further failure, except in the case of scheduled surgery outside the visit dates).
  • Patients under guardianship, curatorship or safeguard of justice
  • Patients not affiliated to the French health insurance system
  • Pregnant women or women of childbearing age without proof of the absence of a current pregnancy

Group 3

  • Subjects with a contraindication to MRI scans
  • Epileptic seizures during the week preceding inclusion:
  • Single seizure: if no rapid return to usual state of consciousness for > 12 hours
  • > 2 separate comitial seizures regardless of duration of loss of consciousness
  • Epileptic malaise
  • Post-anoxic coma with bilateral abolition of N20 cortical responses to SEP
  • Coma related to a potentially recurrent cause of coma (tumour, infection with risk of relapse and inflammation)
  • Moribund patients (life expectancy < 24 hours) or patients undergoing WSLT with a high risk of death before the end of the study (inclusion possible if no therapeutic escalation is decided in a stabilised patient).
  • Haemodynamic or respiratory instability incompatible with prolonged evaluation of the absence of sedation (risk of general anaesthesia for further failure, except in the case of scheduled surgery outside the visit dates).
  • Patients under guardianship, curatorship or safeguard of justice prior to the event that provoked their state of chronic disturbance of consciousness. Patients under guardianship because of their chronic disorder of consciousness are eligible for the study.
  • Patients not affiliated to the French health insurance system
  • Pregnant women or women of childbearing age without proof of the absence of a current pregnancy

Treatment and study plan

Repeated behavioural assessment

Behavioral

One CRS-R per visit

  • 4 SECONDs
  • Eye tracking during every clinical assessment
  • Recording every 2-4h of the Glasgow Coma Score
  • Recording every 2h of the temperature and pupillometer reactivity to light

Act-Pass paradigm

Behavioral

Before and after sedation withdrawal Assessment of infra-clinical response to an active paradigm (attention focalisation or diversion).

Biological measures of circadian and monoamines biomarkers

Behavioral

Systematic urinary sampling every 2 hours for melatonin, cortisol and monoamines metabolites

Transcriptomic and genomic analysis

Behavioral

Definition of the peripheral cellular clock by 2 transcriptomic measures Constitution of a genomic biobank to analyse the cofounding factors for circadian disruption and differential clinical recovery

Polysomnography with concomitant environment recording

Behavioral

One 48h polysomnography for the first visit

+ 3* 24h polysomnography for each visit Synchronised recordings of light, sound, activity in patients' rooms

Actimetry

Behavioral

Continuous recording of movements at the wrist during 7 days after sedation withdrawal

Morphological MRI

Behavioral

Precise description of brain lesion by a 3T MRI within the 1st week after sedation withdrawal

Assessment of correlation between patients' behaviour and neurophysiological markers of consciousness.

Behavioral

Video recording of spontaneous patients' movements in the bed and synchronized during 2h with high-density EEG.

Primary outcomes

  1. Consciousness outcome

    Time frame: 2, 3, 4,6 months post injury

    Coma Recovery Scale - revised used to define 4 possible consciousness outcomes (the best observed before death if the patient died at the date of assessment):

    • Coma
    • Unresponsive Wakefulness Syndrome
    • Minimally Conscious State
    • Exit-Minimally Conscious State (conscious patient)

Secondary outcomes

  1. Functional outcome

    Time frame: GOS: 2, 3, 4,6 months post injury GOSE: 6 months post injury

    Glasgow Outcome Scale (GOS) Glasgow Outcome Scale Extended (GOSE)

    Minimum score 1 and maximum score 5. The lowest score is 5.

  2. Cognitive outcome

    Time frame: 6 months post injury

    MOCA scale

    The MOCA is a short 30-question test that assesses several cognitive domains and allows for early detection of cognitive disorders. The MOCA test takes about 10-15 minutes to administer and consists of several sections, the first of which is an assessment of orientation in time and space. Then there are tasks that assess memory, concentration and reasoning ability, as well as language and visuospatial ability tasks.

    The MOCA score can range from 0 to 30 points, with a score of 26 points or more considered normal.

  3. Quality of life outcome SF-36 scale

    Time frame: 6 months post injury

    At the end, a score for each dimension of the SF-36 was calculated, ranging from 0 to 100. A low score reflects a perception of poor health, loss of function, presence of pain. A high score reflects a perception of good health, absence of functional deficit, and pain (3,6,7)

Study contacts

Contact information is provided by the study sponsor or research team.

GOBERT FLORENT, M.D. Ph.D.

CONTACT

[email protected]

0472681296 ext. +33

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Acronym: COMARHYTHM

Important dates

Study start
2024
Primary completion
2029
Study completion
2029
First posted
Feb 7, 2024
Registry last updated
Jul 30, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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