Multimodal Assessment and Prognosis in Disorders of Consciousness After Severe Brain Injury (CyDoC-MAP) (CyDoC-MAP)

July 27, 2026 updated by: Constantinos Picolas, MD MA, Nicosia General Hospital

Cyprus Disorders of Consciousness - Multimodal Assessment and Prognosis Study: A Single-Centre Prospective Observational Cohort Study of Clinical, Biochemical, Electrophysiological and Imaging Predictors of Long-Term Outcome After Severe Traumatic Brain Injury or Haemorrhagic Stroke

After a severe brain injury some patients survive but cannot communicate, and deciding early which of them are likely to recover consciousness remains one of the hardest problems in neurocritical care. Bedside examination alone misclassifies a substantial proportion of these patients.

CyDoC-MAP is a single-centre, prospective, observational cohort study conducted at Nicosia General Hospital, the sole trauma referral centre for Cyprus. It enrols patients aged 16 years or older who are intubated within 24 hours of a moderate-to-severe traumatic brain injury or a haemorrhagic stroke (intracerebral or subarachnoid haemorrhage), and who are subsequently classified as being in a vegetative state / unresponsive wakefulness syndrome (VS/UWS) or a minimally conscious state (MCS) on the Coma Recovery Scale-Revised (CRS-R).

Four assessment modalities are recorded: (1) the CRS-R, performed at least twice with an interval of at least 48 hours; (2) serum neuron-specific enolase (NSE) sampled within 24 hours of intubation; (3) the bispectral index (BIS), recorded at least twice with an interval of at least 48 hours, after five minutes of standardised noxious and auditory stimulation; and (4) in the traumatic subgroup only, 1.5 T magnetic resonance imaging performed 7-28 days after injury and graded 1-4 by lesion depth by two independent raters.

Level of consciousness is reassessed with the CRS-R 6 to 12 months after the index event, and the total CRS-R score (0-23) at that reassessment is the primary outcome. The primary aim is to estimate the strength of the association between the bispectral index recorded on the ward and that later CRS-R score, and to quantify what the bispectral index adds beyond the baseline clinical assessment. The number of eligible patients at a single national centre does not support the development of a prognostic model; the study is designed to produce effect-size estimates with confidence intervals that will inform a subsequent multicentre study.

The study is purely observational. No intervention is administered, no study procedure alters clinical management, and transfer to rehabilitation is never delayed for research purposes.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Detailed Description

Background. Functional neuroimaging has shown that a proportion of patients who meet the clinical criteria for a vegetative state retain detectable, volitional brain responses to command - the phenomenon of cognitive motor dissociation (CMD). A recent multicentre study reported CMD in approximately one quarter of behaviourally unresponsive patients, with marked variation between centres. Cyprus has no established diagnostic pathway for disorders of consciousness and no locally available specialised rehabilitation service for this population.

Design. Single-centre, prospective, observational cohort study. No randomisation and no intervention. Patients are identified in the intensive care unit and formally entered into the study once they are transferred to the Neurosurgical or Neurological ward and a disorder of consciousness is documented with the CRS-R. The single exception to this sequence is the NSE biomarker, for which venous blood is drawn within 24 hours of intubation.

Assessment schedule. Step 1 - Enrolment and screening: patients aged 16 years or older with traumatic brain injury or haemorrhagic stroke, intubated for a disorder of consciousness within 24 hours of the event; exclusion criteria applied. Step 2 - Acute phase (ICU, within 24 hours of intubation): venous sample for serum neuron-specific enolase. Step 3 - Ward baseline: CRS-R and BIS, each at least twice with an interval of at least 48 hours; classification as VS/UWS or MCS. BIS is recorded after five minutes of noxious and auditory stimulation to avoid falsely low values due to drowsiness; the highest value is recorded. The CRS-R is administered by the study neurologist or speech and language therapist, with attention to sedation, sepsis, subclinical seizures and environmental confounders; the highest score is recorded. Step 4 - Subacute phase (7-28 days after injury, traumatic subgroup only): 1.5 T MRI with T2/FLAIR, DWI, T2*GRE and SWI sequences; lesions graded 1-4 by depth (cortex / white matter; corpus callosum, basal ganglia, thalamus; brainstem; substantia nigra / mesencephalic tegmentum) by two independent raters, with disagreements resolved by consensus. The timing allows postoperative changes to resolve and intracranial pressure to stabilise. Step 5 - Follow-up (6-12 months after the index event): reassessment with the CRS-R; outcome classified as VS/UWS, MCS or eMCS.

Statistical analysis. The analysis is pre-specified in a signed Statistical Analysis Plan (SAP-01) dated before the enrolment of the first patient. The primary outcome is the total CRS-R score (0-23) at 6-12 months, treated as a continuous variable; the VS/UWS-MCS-eMCS classification is retained as a secondary outcome. The highest bispectral index value is designated in advance as the primary prognostic marker, because it is the novel element of the study and the only marker whose measurement is guaranteed in every enrolled patient. The single hypothesis test is the Spearman rank correlation between the highest bispectral index and the total CRS-R score at follow-up, reported with a 95% confidence interval, alongside a simple linear regression estimating the slope. One secondary pre-specified analysis adds the baseline total CRS-R as a second predictor and reports the incremental explained variance; no further predictor enters that model. Serum neuron-specific enolase, MRI lesion depth grade, age, pre-intubation Glasgow Coma Scale and intensive care length of stay are analysed on an exploratory basis only, without correction for multiple comparisons and without conclusions. The anatomical distribution of MRI lesions is presented descriptively, by site and side, with no significance testing. Inter-rater reliability of the MRI grading is expressed as weighted Kappa. Development of a multivariable prognostic model, stepwise or automated variable selection, searching for an optimal bispectral index cut-off, and dichotomisation of continuous variables are excluded at the outset: with 30-40 patients and an expected 10-18 outcome events, current sample-size criteria for prediction-model development require approximately 320-385 patients. The study is therefore reported as a study of prognostic associations and feasibility, not as prognostic model development.

Ethics and data protection. Approved unanimously by the Cyprus National Bioethics Committee (protocol EEBK/EP 2025/47) on 10 July 2026. Written informed consent is obtained from the next of kin. Data are pseudonymised at the point of collection; no names or direct identifiers are held in the study database. Data handling complies with the EU General Data Protection Regulation, and records are retained for eight years from the start of the study and are then destroyed.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

  • Name: Iakovos Lytrides, MD MSc

Study Locations

  • Cyprus
      • Nicosia, Cyprus, 2029
        • Nicosia General Hospital, Department of Neurosurgery
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Consecutive patients aged 16 years or older admitted or transferred to Nicosia General Hospital with a disorder of consciousness following moderate-to-severe traumatic brain injury or haemorrhagic stroke, who required intubation within 24 hours of the index event and who are classified as VS/UWS or MCS on the Coma Recovery Scale-Revised.

Description

Inclusion Criteria:

  • Inclusion Criteria:
  • Age 16 years or older
  • Moderate-to-severe traumatic brain injury, or haemorrhagic stroke (intracerebral or subarachnoid haemorrhage)
  • Intubation for a reduced level of consciousness within 24 hours of the index event
  • Admitted to, or transferred to, Nicosia General Hospital
  • Classified as VS/UWS or MCS on the Coma Recovery Scale-Revised after discharge from the intensive care unit
  • Written informed consent obtained from the next of kin (and from a legal guardian for participants aged 16-17)

Exclusion Criteria:

  • Severe pre-existing psychiatric disorder
  • History of ischaemic or haemorrhagic stroke
  • Pre-existing dementia
  • Reduction in Glasgow Coma Scale attributable to sedation or intoxicating substances
  • Reduction in Glasgow Coma Scale attributable to severe extracranial injury (massive haemorrhage, generalised hypoxia)
  • End-stage disease with a life expectancy of less than 6 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
VS/UWS
Patients classified as being in a vegetative state / unresponsive wakefulness syndrome on the Coma Recovery Scale-Revised at ward baseline.
MCS
Patients classified as being in a minimally conscious state (MCS- or MCS+) on the Coma Recovery Scale-Revised at ward baseline.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Total Coma Recovery Scale-Revised (CRS-R) score at 6-12 months
Time Frame: 6 to 12 months after the index event
Total score on the Coma Recovery Scale-Revised at the 6-12 month reassessment, treated as a continuous variable. The CRS-R comprises six subscales (auditory, visual, motor, oromotor/verbal, communication and arousal); the total score ranges from 0 (worst) to 23 (best). The pre-specified primary analysis is the Spearman rank correlation between this score and the highest bispectral index value recorded at ward baseline, reported with a 95% confidence interval. Death before follow-up is reported separately and is not coded as a score of 0 in the primary analysis; a pre-specified sensitivity analysis assigns a value of 0 to those who died.
6 to 12 months after the index event

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
CRS-R diagnostic category at 6-12 months
Time Frame: Ward baseline to 6-12 months
Classification derived from the Coma Recovery Scale-Revised at follow-up as vegetative state / unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS) or emergence from the minimally conscious state (eMCS) - the clinically legible form of the primary outcome. Transitions between the ward baseline category and the follow-up category are presented descriptively, including the proportion of patients classified as VS/UWS at baseline who reach MCS or eMCS.
Ward baseline to 6-12 months
Serum neuron-specific enolase (NSE) - exploratory
Time Frame: Within 24 hours of intubation to 6-12 months
Correlation between the serum NSE concentration (microgram/L) obtained within 24 hours of intubation and the total CRS-R score at follow-up, with a 95% confidence interval. Exploratory only: no correction for multiple comparisons is applied and no conclusion is drawn. The assay is not guaranteed in every enrolled patient, so the number of available observations is stated in every related table.
Within 24 hours of intubation to 6-12 months
Incremental value of the bispectral index beyond the baseline clinical assessment
Time Frame: Ward baseline to 6-12 months
Incremental explained variance (delta R-squared), with a confidence interval, from a linear regression of the total CRS-R score at follow-up on two predictors only: the highest bispectral index value and the baseline total CRS-R score. No further predictor enters this model. The analysis is stated in advance to be underpowered - an incremental contribution of the order of 15% is detectable at the anticipated sample size, whereas 10% is not - and a negative result will not be interpreted as evidence of absence of effect.
Ward baseline to 6-12 months
MRI lesion depth grade, traumatic subgroup - exploratory
Time Frame: 7-28 days after injury to 6-12 months
Correlation between the 1-4 lesion depth grade on 1.5 T MRI obtained 7-28 days after injury and the total CRS-R score at follow-up, in patients with traumatic brain injury (anticipated approximately 20). Exploratory only, without correction for multiple comparisons. In the non-traumatic group these data are characterised as structurally not applicable rather than missing, since MRI is performed by design only after trauma.
7-28 days after injury to 6-12 months
Anatomical distribution of MRI lesions - descriptive only
Time Frame: 7-28 days after injury to 6-12 months
Presence and side (right, left or bilateral) of lesions at seven anatomical sites - cerebral cortex or lobar white matter, corpus callosum, basal ganglia, thalamus, brainstem (pons, medulla, cerebral peduncles), substantia nigra and midbrain tegmentum - recorded by consensus of the two raters. Presented as a per-patient table and as frequencies per site cross-tabulated with outcome category. Explicitly descriptive: no p-values, no chi-square or Fisher test, and no claim of association. The 1-4 grade is hierarchical and retains only the deepest lesion, so site-by-site recording preserves information that would otherwise be lost at the moment the form is completed.
7-28 days after injury to 6-12 months
Inter-rater reliability of MRI lesion depth grading
Time Frame: 7-28 days after injury
Agreement between the two independent raters on the 1-4 lesion depth grade, expressed as a linearly weighted Kappa given the ordinal nature of the grade, with disagreements resolved by consensus. Where independent duplicate CRS-R assessments exist, the intraclass correlation coefficient for the total score is also reported. Both with 95% confidence intervals.
7-28 days after injury

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Nicosia General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 15, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 15, 2030

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 30, 2030

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 27, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 27, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 30, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 30, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 27, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CyDoC-MAP-2025-47
  • EEBK/EP 2025/47 (Other Identifier: Cyprus National Bioethics Committee)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

A decision on sharing individual participant data will be made after the primary publication. The cohort is small and is drawn from the single national referral centre of a small population, so any sharing would first require an assessment of the residual risk of re-identification. The approved informed-consent documents do not currently cover onward sharing of individual-level data. Data are held pseudonymised and are destroyed eight years after the start of the study.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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