Co-ultra PEALut Enhances Neuronal Recovery Following Moderate Traumatic Brain Injury (GLIA13)

Traumatic brain injury (TBI) typically provokes secondary injury mechanisms, including the dynamic interplay between the ischemic, inflammatory, and cytotoxic processes. Moreover, such an impact induces a substantial level of cell death and results in the degeneration of the dendrites, thereby leading to persistent motor, sensory, and cognitive dysfunction. Previous studies have shown that the adult-born immature granule neurons in the dentate gyrus are the most susceptible of all the cell types in the hippocampus to damage following a moderate TBI due to a controlled cortical impact (CCI) device. Currently, there is no efficient approach available for avoiding immature neuron death or degeneration following TBI. Hence, this study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), which is composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of TBI, as well as in patients affected by TBI.

Study Setting All patients affected by moderate TBI (Glasgow Coma Score 9-13) admitted to the neurosurgical department of the University Hospital of Messina, Italy, will be screened for recruitment. Ethics The institutional review board (IRB) approved the study. Written consent will be obtained from each patient or the closest family member prior to the start of the study. Study Design A randomized controlled single-blind study to assess the effects of co-ultraPEALut (Glialia®) administration in TBI patients will be carried out. The study is set to recruit at least 30 patients. Recruited patients are randomly allocated to one of the two branches of the study: standard TBI treatment + Glialia® (Study Group) and standard TBI treatment (Control Group) in a 1:1 ratio using precompiled randomization tables. General treatment All patients will undergo standard treatments according to patterns of severity and in the light of distinct variables, mainly represented by the conditions of cerebral hemodynamics. These procedures can be summarized as follows: Surgical evacuation of hemorrhagic masses and / or "debridement" of outbreaks brain contusion; Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Goals were a systolic blood pressure >90 mmHg and a cerebral perfusion pressure >60 mmHg. Prevention of secondary complications of critical illness included: preventive therapy of venous thromboembolism (VTE) using low molecular weight heparin (LMWH) and seizures using levetiracetam prophylactically for the first seven days after injury; Patient who underwent surgical treatment, received also postoperative intensive care treatments including: position of the head high, lower values of end-tidal CO2, sedation with reduced metabolic consumption of O2, increase in plasma osmolarity by administration of mannitol in controlled doses or hypernatremia, therapeutic CSF drainage. Specific Treatment The investigations agent, the co-ultraPEALut, will be administered orally twice daily (every 12 h) for 180 days in association with the specific therapy (e.g., antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial hypertension).

All patients are treated by standard treatments according to patterns of severity and in the light of different variables, mainly represented by the conditions of cerebral hemodynamics. These procedures can be summarized as follows: Surgical evacuation of hemorrhagic masses and brain contusion Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Prevention of secondary complications of critical illness included: preventive treatment of venous thromboembolism (VTE) and seizures Patient who undergo surgical treatment, will recieve also postoperative intensive care treatments including: position of the head high, lower values of end-tidal CO2, sedation with reduced metabolic consumption of O2, increase in plasma osmolarity by administration of mannitol in controlled doses or hypernatremia, therapeutic CSF drainage

Standard treatment plus specific treatment. The investigational agent, the co-ultraPEALut, is administered orally twice daily (every 12 h) for 180 days in association with the specific therapy (e.g., antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial hypertension).

Impairment of cognitive abilities will be evaluated by the Mini Mental State Examination (MMSE) (Folstein et al., 1975) adjusted for educational level and age. This is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia. It is also used to estimate the severity and progression of cognitive impairment and to follow the course of cognitive changes in an individual over time that is within the scope of this research. The threshold value for normal performance is set to 24 points. The outcome measure will be represented by the absolute score and by the change between the score recorded after 180 days and the baseline value

All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)

Brief Neuropsychological Cognitive Examination (BNCE) (Ball et al., 2009). This consists in 10 subtests composed of easily administered tasks, none requiring more than minimal reading skills.Total score indicating overall severity of impairment (expressed in percentage), subtest scores, and two aggregate scores for the simple and complex subtests are provided as percentage of the maximum score. The outcome measure will be represented by the absolute score and by the difference between the score recorded after 180 days and the baseline value

All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)

Depression will be assessed by the Beck inventory depression scale.This is a 21-question multiple-choice (scored 0-3 each) self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Scores will be categorized as follows: 0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression Depression score will be assessed at 180 days (T180) after trauma

Independence in activities of daily living and self-care will be assessed by the Barthel Index. This is an ordinal scale used to measure performance in activities of daily living (ADL). Each performance item is rated on this scale with a given number of points assigned to each level or ranking. Each domain is scored in one-point increments with a full score of 20 indicating functional independence. Independence will be assessed at 180 days (T180) after trauma

Inclusion Criteria: Traumatic brain injuries Moderate trauma Glasgow Coma Score 9-13 Loss of consciousness lasting >1 min post-traumatic amnesia >20 minutes CT scan Marshall Scale class II-VI. Exclusion Criteria: Spinal cord injuries Pre-existing neurological disorders affecting the brain and/or the spinal cord Severe hypertension Diabetes, and chronic renal disease Remarkable chronic cerebravasculopathy of the CT Severe cognitive deficit.