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

• ClinicalTrials.gov Identifier: NCT04495192
• Recruitment Status: Recruiting
• First Posted: July 31, 2020
• Last Update Posted: August 5, 2020
• Sponsor: Fondazione Don Carlo Gnocchi Onlus
• 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

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 *

• Bernat JL. Chronic disorders of consciousness. Lancet. 2006 Apr 8;367(9517):1181-92. doi: 10.1016/S0140-6736(06)68508-5. Erratum In: Lancet. 2006 Jun 24;367(9528):2060.
• Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, Kelly JP, Rosenberg JH, Whyte J, Zafonte RD, Zasler ND. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002 Feb 12;58(3):349-53. doi: 10.1212/wnl.58.3.349.
• Hirschberg R, Giacino JT. The vegetative and minimally conscious states: diagnosis, prognosis and treatment. Neurol Clin. 2011 Nov;29(4):773-86. doi: 10.1016/j.ncl.2011.07.009.
• Amantini A, Grippo A, Fossi S, Cesaretti C, Piccioli A, Peris A, Ragazzoni A, Pinto F. Prediction of 'awakening' and outcome in prolonged acute coma from severe traumatic brain injury: evidence for validity of short latency SEPs. Clin Neurophysiol. 2005 Jan;116(1):229-35. doi: 10.1016/j.clinph.2004.07.008.
• Cavinato M, Freo U, Ori C, Zorzi M, Tonin P, Piccione F, Merico A. Post-acute P300 predicts recovery of consciousness from traumatic vegetative state. Brain Inj. 2009 Nov;23(12):973-80. doi: 10.3109/02699050903373493.
• Portaccio E, Morrocchesi A, Romoli AM, Hakiki B, Taglioli MP, Lippi E, Di Renzone M, Grippo A, Macchi C; Intensive Rehabilitation Unit Study Group of the IRCCS Don Gnocchi Foundation, Italy. Improvement on the Coma Recovery Scale-Revised During the First Four Weeks of Hospital Stay Predicts Outcome at Discharge in Intensive Rehabilitation After Severe Brain Injury. Arch Phys Med Rehabil. 2018 May;99(5):914-919. doi: 10.1016/j.apmr.2018.01.015. Epub 2018 Feb 8.
• Portaccio E, Morrocchesi A, Romoli AM, Hakiki B, Taglioli MP, Lippi E, Di Renzone M, Grippo A, Macchi C. Score on Coma Recovery Scale-Revised at admission predicts outcome at discharge in intensive rehabilitation after severe brain injury. Brain Inj. 2018;32(6):730-734. doi: 10.1080/02699052.2018.1440420. Epub 2018 Feb 26.
• Scarpino M, Lolli F, Hakiki B, Atzori T, Lanzo G, Sterpu R, Portaccio E, Romoli AM, Morrocchesi A, Amantini A, Macchi C, Grippo A; Intensive Rehabilitation Unit Study Group of the IRCCS Don Gnocchi Foundation, Italy. Prognostic value of post-acute EEG in severe disorders of consciousness, using American Clinical Neurophysiology Society terminology. Neurophysiol Clin. 2019 Sep;49(4):317-327. doi: 10.1016/j.neucli.2019.07.001. Epub 2019 Jul 18.
• Lammi MH, Smith VH, Tate RL, Taylor CM. The minimally conscious state and recovery potential: a follow-up study 2 to 5 years after traumatic brain injury. Arch Phys Med Rehabil. 2005 Apr;86(4):746-54. doi: 10.1016/j.apmr.2004.11.004.
• Katz DI, Polyak M, Coughlan D, Nichols M, Roche A. Natural history of recovery from brain injury after prolonged disorders of consciousness: outcome of patients admitted to inpatient rehabilitation with 1-4 year follow-up. Prog Brain Res. 2009;177:73-88. doi: 10.1016/S0079-6123(09)17707-5.
• Estraneo A, Moretta P, Loreto V, Lanzillo B, Santoro L, Trojano L. Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology. 2010 Jul 20;75(3):239-45. doi: 10.1212/WNL.0b013e3181e8e8cc. Epub 2010 Jun 16.
• Lipsky RH, Lin M. Genetic predictors of outcome following traumatic brain injury. Handb Clin Neurol. 2015;127:23-41. doi: 10.1016/B978-0-444-52892-6.00003-9.
• Kim BR, Kim HY, Chun YI, Yun YM, Kim H, Choi DH, Lee J. Association between genetic variation in the dopamine system and motor recovery after stroke. Restor Neurol Neurosci. 2016 Nov 22;34(6):925-934. doi: 10.3233/RNN-160667.
• Sorbi S, Nacmias B, Piacentini S, Repice A, Latorraca S, Forleo P, Amaducci L. ApoE as a prognostic factor for post-traumatic coma. Nat Med. 1995 Sep;1(9):852. doi: 10.1038/nm0995-852. No abstract available.
• Lanzillotta A, Pignataro G, Branca C, Cuomo O, Sarnico I, Benarese M, Annunziato L, Spano P, Pizzi M. Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiol Dis. 2013 Jan;49:177-89. doi: 10.1016/j.nbd.2012.08.018. Epub 2012 Aug 30.
• Thelin EP, Nelson DW, Vehvilainen J, Nystrom H, Kivisaari R, Siironen J, Svensson M, Skrifvars MB, Bellander BM, Raj R. Evaluation of novel computerized tomography scoring systems in human traumatic brain injury: An observational, multicenter study. PLoS Med. 2017 Aug 3;14(8):e1002368. doi: 10.1371/journal.pmed.1002368. eCollection 2017 Aug. Erratum In: PLoS Med. 2023 Nov 28;20(11):e1004320.
• Mateen BA, Hill CS, Biddie SC, Menon DK. DNA Methylation: Basic Biology and Application to Traumatic Brain Injury. J Neurotrauma. 2017 Aug 15;34(16):2379-2388. doi: 10.1089/neu.2017.5007. Epub 2017 Jun 28.
• Scarpino M, Lolli F, Hakiki B, Lanzo G, Sterpu R, Atzori T, Portaccio E, Draghi F, Amantini A, Grippo A; Intensive Rehabilitation Unit Study Group of the IRCCS Don Gnocchi Foundation, Italy. EEG and Coma Recovery Scale-Revised prediction of neurological outcome in Disorder of Consciousness patients. Acta Neurol Scand. 2020 Sep;142(3):221-228. doi: 10.1111/ane.13247. Epub 2020 Apr 14.

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

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

• Current Responsible Party: Bahia Hakiki, Fondazione Don Carlo Gnocchi Onlus
• Original Responsible Party: Same as current
• Current Study Sponsor: Fondazione Don Carlo Gnocchi Onlus
• Original Study Sponsor: Same as current
• 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