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Predictors of Better Outcomes After Severe Acquired Brain Injuries (FP-GCA)

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ClinicalTrials.gov Identifier: NCT04495192
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : August 5, 2020
Sponsor:
Information provided by (Responsible Party):
Bahia Hakiki, Fondazione Don Carlo Gnocchi Onlus

Tracking Information
First Submitted Date July 17, 2020
First Posted Date July 31, 2020
Last Update Posted Date August 5, 2020
Actual Study Start Date June 9, 2020
Estimated Primary Completion Date June 10, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 30, 2020)
  • Consciousness recovery [ Time Frame: 24 months ]
    The Consciousness recovery will be measured throught the italian version of the CRS-R performed for at least 5 time during one week to avoid a misdiagnosis due to consciousness fluctuations.Consciousness recovery is defined as CRS_R >23 and Improvement Responsiveness will be registred for patients transitioning from UWS to MCS or E-MCS, and from MCS to E-MCS.
  • Tracheostomy weaning [ Time Frame: 24 months ]
    Tracheostomy weaning will be reported as a dichotomic variable: decannulated yes/no
  • Total oral feeding recovery [ Time Frame: 24 months ]
    The swallowing severity will be assessed throught the Oral feeding recovery measured by Functional Oral Intake Scale (FOIS) scoring from 1 (severe dysphagia) to 7(absence of dysphagia). The outcome of "oral feeding recovery" corrispond to Functional Oral Intake Scale>4
  • Functional autonomy [ Time Frame: 24 months ]
    Functional autonomy measured by Glasgow Outcome Scale Expanded scoring between 1 (death) and 8 (complete functional recovery). A good autonomy is defined for Glasgow Outcome Scale Expanded >4
  • Time to decannulation [ Time Frame: 24 months ]
    In decannulated patients, time between admission in the IRU and decannulation will be reported
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: August 4, 2020)
  • Cognitive profile [ Time Frame: 24 months ]
    The cognitive profile will be assessed firstly investigating the "post-event amnesia" by the Galveston Orientation & Amnesia Test. The date of "post-event amnesia" resolution will be reported when the Galveston Orientation & Amnesia Test score >75 for two consecutive days
  • Degree of social and occupational reintegration [ Time Frame: 24 months ]
    Degree of social and occupational reintegration assessed by the Community Integration Questionnaire (CIQ). Minimum score is 10 and maximum score is 50. A higher score indicates a higher comunity integration
  • Subjective and Objective Quality Of Life [ Time Frame: 24 months ]
    The Quality of Life after Brain Injury (QoLibri) scale allows to measure both the quality of life perceived by both the patient and the caregiver. Quality of Life after Brain Injury (QoLibri) scores are reported on a 0-100 scale. 0=worst possible quality of life and 100=best possible quality of life.
Original Secondary Outcome Measures
 (submitted: July 30, 2020)
  • Cognitive profile [ Time Frame: 24 months ]
    The cognitive profile will be assessed firstly investigating the "post-event amnesia" by the Galveston Orientation & Amnesia Test. The date of "post-event amnesia" resolution will be reported when the Galveston Orientation & Amnesia Test score >75 for two consecutive days
  • Degree of social and occupational reintegration [ Time Frame: 24 months ]
    Degree of social and occupational reintegration assessed by the Community Integration Questionnaire (CIQ). Minimum score is 10 and maximum score is 50. A higher score indicates a higher comunity integration
  • Quality Of Life [ Time Frame: 24 months ]
    Quality of Life after Brain Injury scores are reported on a 0-100 scale 0=worst possible quality of life and 100=best possible quality of life.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Predictors of Better Outcomes After Severe Acquired Brain Injuries
Official Title Clinical, Neurophysiological and Genetical Predictors of Consciousness Recovery and Functional Outcomes After Severe Acquired Brain Injuries
Brief Summary Severe Acquired Brain Injury is defined as a traumatic, post-anoxic, vascular or other brain damage that causes coma for at least 24 hours and leads to permanent disability with sensorial, motor, cognitive or compartmental impairment. In this context, an accurate characterization of individual patients' profile in terms of neuronal damage, potential for neuroplasticity, neurofunctional and clinical state could allow to plan tailored rehabilitation and care pathway on the basis of solid prognostic information, also for optimizing resources of the National Health care systems and enhance ethical decisions. Patient profiling should encompass measures and procedures easily available at the bedside, and with affordable time, resource, and money-costs to determine a real impact on National Health systems. The aim of the study is identifying patient profiles in terms of clinical, neurophysiological and genetical aspects with better long-term outcome in order to plan tailored therapeutic interventions.
Detailed Description

Background:

After a severe Acquired Brain Injury (sABI) the consciousness, the functional and the cognitive recovery of the patients depends on the severity of the damage suffered but also on the vulnerability of the individual brain. Some patients with sABI may survive in a state of Disorder of Consciousness (DoC) condition (i.e., patients in vegetative state/unresponsive wakefulness syndrome, VS/UWS or in minimally conscious state, MCS). Other patients, despite having a complete recovery of consciousness, can reach very variable degrees of functional and cognitive autonomy. The prognostic factors of consciousness recovery of patients with DoCs have been thoroughly investigated. Most of these studies investigated the acute phase, while only a few studies have examined the role of early clinical factors emerging before the complete recovery of consciousness . Further prognostic insights can be provided by analysis of genes coding for Apolipoprotein E (APOE), dopamineD2 receptor (DRD2), and Brain Derived Neutrophic Factors (BDNF), and by markers of axonal injury.

Study aim:

The present project aims at identifying patient profiles with better long-term outcome in order to plan tailored therapeutic interventions.

The patient profiles will be drawn up by gathering patient's demographic (age, gender, social and educational level), anamnestic (aetiology and time post-brain injury, Cognitive Reserve Index), clinical state (Cumulative Illness Rating Scale (CIRS), CRS-R total score and corresponding consciousness state; Disability Rating Scale, DRS, Functional Oral Intake Scale; FOIS, Glasgow Outcome Scale Expanded; GOS-E, Level of Cognitive Functioning; LCF) and neurophysiological data (Electroencephalogram (EEG), Somatosensory evoked potentials (SEP), and Motor evoked potentials (MEP) nerve conduction aimed at evaluating occurrence of critical illness polyneuropathy and myopathy (CIPNM)) at study entry (baseline), together with neural biomarkers (genetic markers).

On the basis of the above mentioned stratification of patients by this multimodal approach, the present study aimed to

  1. Investigate the possible association of certain profiles with the consciousness recovery at the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2 years from the acute event
  2. Investigate the possible association of certain profiles with the functional outcomes at the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2 years from the acute event.
  3. Investigate the possible association of certain profiles with the long-term cognitive profile and the level of familiar and social participation at 1 year and 2 years from the acute event.

Setting , population and methods:

The proposed study is a longitudinal multi-location prospective observational cohort study.

Four centers of the Don Carlo Gnocchi Foundation will participate (Florence, La Spezia, Milan and Sant'Angelo dei Lombardi and the neurogenetics laboratory of the University of Florence, Department of Medical and Experimental Sciences, Neurology). The enrollment phase will last 3 years (June 2020-June 2023). 520 patients with severe brain injury will be included (200 for the Florence and La Spezia units and 60 for the Milan and Sant'Angelo dei Lombardi units).

All patients admitted in the participant IRU with a history of sABI within 4 months, aged 18+, presenting a signed informed consent signature for the participation to the study and for the genetic analysis will be consecutively enrolled.

A multidimodal evaluation including clinical examinations and neurophysiological assessments will be performed by skilled professionals. The study foresees four steps in the late acute phase and two in the long-term phase: 1) at the study entry time (T0), 2) at three months from T0 (T1) 3) at 6 months from T0 (T2) 4) at discharge (T3) 5) at 12 months from the acute event (T4) 6) at 24 months from the acute event.

Clinical assessment including :

  1. Consciousness assessment using CRS-R
  2. Care severity profile: including the comorbidity assessed thought the Cumulative Illness Rating Scale (CIRS), the presence of medical devices, sepsis occurrence during the IRU stay, neurosurgery interventions, bedsores, epileptic event and other complications
  3. Functional evaluation using the following scales: ERBI, GOS-E, DRS, FIM, PAINED pain scale, TCT, Ashworth, FOIS
  4. Neurocognitive profile evaluation using the Galveston Orientation and Amnesia Test (GOAT), the Level of Cognitive Functioning (LCF) and the International Classification of Functioning, Disability and Health (ICF), ABS, AES and Cognitive Reserve Index (CRI)

Multimodal neurophysiological evaluation including:

  1. Standard EEG recording at rest. EEG background activity and reactivity will be classified according to recently proposed diagnostic criteria for DoC and to American Clinical Neurophysiology Society Critical Care EEG Terminology.
  2. Motor and sensory nerve conduction studies. Sensory nerve action potentials, and compound muscle action potentials (CMAP) will be evaluated. Muscular activity at rest and when possible during reflex contraction will be assessed.
  3. PEM: Transcranial magnetic stimulation (TMS) will be performed according to the standard criteria of the International Federation of Clinical Neurophysiology. MEP will be recorded from abductor digiti minimi and tibialis anterior muscles and size of MEP measured as MEP/CMAP amplitude ratio.
  4. Bilateral upper limb SEP will be recorded according to the International Federation of Clinical Neurophysiology. The presence or absence of N20/P25 cortical components will be evaluated.

Genetic assessment Genomic DNA will be obtained from EDTA-whole venous blood sample by Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes will be performed by high resolution melt (HRM) analyses and direct sequencing on Automatic Genetic Analyzer. APOE genotypes will be investigated by HRM with two sets of PCR primers designed to amplify the regions encompassing rs7412 [NC_000019.9: g.45412079C>T] and rs429358 (NC_000019.9: g.45411941T>C). The samples with known ApoE genotypes, which had been validated by DNA sequencing, will be used as standard references. The genetic polymorphism data will be compared to sex- and age-matched control of the DNA banking of the neurogenetic Laboratory of Careggi Hospital of Florence.

Statistic analysis:

All collected data will be analyzed using a machine learning algorithm, creating, for each patient, a risk profile for the possible consciousness recovery and functional autonomy.

On the basis of the results of this study, partecipant will build on a "decision support tool" for future sABI patients afferent to the Intensive Rehabilitative Unit, in order to plan personalized rehabilitative and therapeutic interventions, allowing therefore an optimization of resources (costs and resources) for National Health Service

Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration 24 Months
Biospecimen Retention:   Samples With DNA
Description:
blood
Sampling Method Non-Probability Sample
Study Population Patients with severe Acquired Brain Injuries admitted in the Intensive Rehabilitative Unit (IRU) of the four participant don Gnocchi Foundation Centers (Florence, La Spezia, Milano and Sant'Angelo dei Lombardi) fulfilling the inclusion criteria will be included.
Condition
  • Brain Injuries
  • Disorder of Consciousness
Intervention Genetic: Genetic analysis of different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes assessment
Genomic DNA will be obtained from EDTA-whole venous blood sample by Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes will be performed by HRM analyses and direct sequencing on Automatic Genetic Analyzer. All the aliquots will be amplified by a real-time PCR. The genetic polymorphism data will be compared to sex- and age-matched control of the DNA banking of the neurogenetic Laboratory of Florence Hospital.
Study Groups/Cohorts Patients affected by severe Acquired Brain Injury
All patients admitted in the participant IRU with a history of sABI and fulfilling our inclusion and exclusion criteria will be recruited.
Intervention: Genetic: Genetic analysis of different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes assessment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: July 30, 2020)
520
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 10, 2025
Estimated Primary Completion Date June 10, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • patients admitted with a history of severe Acquired Brain Injury within 4 months,
  • aged 18+,
  • signed informed consent signature for the participation to the study
  • signed informed consent signature for the participation to for the genetic analysis

Exclusion Criteria:

  • patients admitted with a history of severe Acquired Brain Injury more then 4 months
  • Absence of informed consent to participate in the study
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Bahia Hakiki, MD, Phd 0039-333-4018388 bhakiki@dongnocchi.it
Listed Location Countries Italy
Removed Location Countries  
 
Administrative Information
NCT Number NCT04495192
Other Study ID Numbers 16606_OSS
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Bahia Hakiki, Fondazione Don Carlo Gnocchi Onlus
Study Sponsor Fondazione Don Carlo Gnocchi Onlus
Collaborators Not Provided
Investigators
Principal Investigator: Bahia Hakiki, MD, Phd IRCCS Fondazione Don Carlo Gnocchi, Florence
PRS Account Fondazione Don Carlo Gnocchi Onlus
Verification Date July 2020