Biperiden Trial for Epilepsy Prevention (BIPERIDEN)

PROADI-SUS, Ministry of Health, Brazil, Feculdade de Medicina da Universidade de Sao Paulo - Brasil, Santa Casa de Campo Grande, Federal University of São Paulo, Hospital Sao Rafael

One of the most important neurological consequences following Traumatic Brain Injury (TBI) is the development of post traumatic epilepsy (PTE). Nevertheless, there is still no effective therapeutic intervention to reduce the occurrence of PTE. In previous studies with animals models of epilepsy, the biperiden decreased the incidence and intensity of spontaneous epileptic seizures besides delaying their appearance. The aim of this study is the evaluation of biperiden as antiepileptogenic drug to prevent PTE and also the determination of side effects, evaluating its cost-effectiveness in patients with moderate and severe TBI.

One of the most important neurological consequences following Traumatic Brain Injury (TBI) is the development of post traumatic epilepsy (PTE), which accounts for 5% of all epilepsy etiologies in the general population. This makes TBI one of the most important causes of secondary epilepsy, overcoming other causes such as infections, drug abuse or familiar history of epilepsy. The occurrence of spontaneous epileptic seizures after TBI, mostly starting in the first 2 years after moderate or severe TBI, might be as high as 86%, specially in those with a single acute symptomatic seizure, with remission rates of 25-40%. The causative relationship between TBI and epilepsy, as well as other types of epilepsy in general, are still not completely understood and PTE is not yet preventable. The therapeutic approach indicated for TBI may involve medications, surgical procedures or both, with no effective therapeutic intervention to reduce its occurrence. Several experimental studies in animal models have shown that drugs, which modify processes of neuronal plasticity, have the potential to modify the natural course of PTE. Among these, biperiden (anti-cholinergic indicated for Parkinson's disease) has shown reduction in the incidence and intensity of spontaneous epileptic seizures and also delayed their occurence in animal epilepsy model. Thus Biperiden would be an excellent candidate for an antiepileptogenic agent. It is intended here to test its effectiveness and safety in adult patients, victims of moderate and severe TBI. Patients will be randomized to receive 5 mg of Biperiden iv, diluted in 100 ml of 0.9% saline (treatment group) or 1 mL of sterile vehicle (sodium lactate, lactic acid, sodium hydroxide and water for injections) diluted in 100 mL of 0,9% saline (placebo group), every 6 hours for 10 days after TBI. Prospectively, patients will be followed up for two years, on periodic visits to assess the development of epileptic seizures. Other factors that might have benefits with the treatment, such as epileptiform abnormalities, genetic markers and neuropsychological aspects, will also be evaluated. The results could be important for a better comprehension of basic mechanisms of epilepsy development. Side effects of Biperiden use, at high doses during a short period of time, will be measured. If Biperiden is efficient and safe, it will certainly be a low-cost option for Brazilian public health system (SUS).

Drug: Biperiden 5mg of biperiden diluted in 100 ml of 0.9% saline - every 6 hours for 10 consecutive days - IV

Placebo 1 mL of sterile vehicle (sodium lactate, lactic acid, sodium hydroxide and water for injections) diluted in 100 mL of 0,9% saline - every 6 hours for 10 consecutive days - IV

1ml sterile vehicle (sodium lactate, lactic acid, sodium hydroxide and water for injections) diluted in 100 ml 0.9% saline - every 6 hours for 10 consecutive days - IV

Participants who present epileptic seizures will be compared between placebo and biperiden groups. Seizures will be counted starting 7 days after TBI and continuously during the following two years follow-up period. Patients and their relatives will be asked to keep a diary of seizures, and record all seizures with detailed descriptions of each event.

Proportion of participants that present at least one severe adverse event until 24 months after the traumatic brain injury will be compared between biperiden and placebo groups.

Electroencephalogram (EEG) will be analysed mostly looking for epileptiform abnormalities and ictal patterns. EEG is going to be recorded at follow-up visits. Data will be compared between placebo and biperiden groups.

Standard neuropsychologic test (Vocabulary) of the Wechsler Intelligence Scale III (WAIS III) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluate the semantic memory. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Block design) of the Wechsler Intelligence Scale III (WAIS III) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the visual construction. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Digit Symbol-Coding and Symbol Search) of the Wechsler Intelligence Scale III (WAIS III) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the information processing speed and attention. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Digit Span) of the Wechsler Intelligence Scale III (WAIS III) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the information processing speed and attention. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Rey-Osterrieth complex figure) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the visual construction and visuospatial long-term memory. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Rey Auditory Verbal Learning Test (RAVLT)) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the verbal long-term memory. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Standard neuropsychologic test (Five Digit Test (FDT)) which will be applied by psychologists at 6 months and then 24 months after TBI. It evaluates the verbal long-term memory. It will be used the percentile scale that varies between 0.1 minimum (worst result) and 99.9 maximum (best result). The results will be compared between biperiden and placebo groups.

Health related quality of life will be evaluated through the portuguese version of EuroQol three-level version (EQ-5D-3L) descriptive system. EQ-5D-3L comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state in each of the five dimensions. The answers given to ED-5D-3L can be converted into EQ-5D index, an utility scores anchored at - 0,78 for the worst health to 1 for perfect health. Results will be compared between biperiden and placebo groups.

Health related quality of life will be evaluated through the portuguese version of EuroQol visual analogue scale (EQ-VAS) which records the patient's self-rated health on a vertical visual analogue scale and it can be used as a quantitative measure of health outcome that reflects the patient's own judgement. EQ-VAS has a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status). Results will be compared between biperiden and placebo groups.

To investigate the expression of the ApoEϵ4 allele in TBI patients, its correlation with post traumatic epilepsy and the biperiden response to prevent epilepsy, RFLP-PCR will be assayed in blood samples of TBI patients. The genotyping reactions will be performed blinded to clinical data. The presence of the ApoEϵ4 allele will be correlated with the incidence of seizures in the follow-up assessments after TBI.

Participants who present epileptic seizures will be compared between placebo and biperiden groups. Seizures will be counted starting 7 days after TBI and continuously during the following two years follow-up period. For each visit after TBI patients and their relatives will be asked about occurrence of seizures and their diary notes of seizures. For all events, a detailed descriptions wiil be asked . Seizures should be classified according to 2017 International League against Epilepsy classification. The recordings will be evaluated in each patient visit. The goal is to define, over time, when epilepsy starts in each group (biperiden and placebo).

Participants who died throughout the period of study (24 months after TBI) will be compared between placebo and biperiden groups. Although patients includes are severe, the effectiveness of biperiden to reduce mortality might be evaluated,

Biperiden and placebo groups will be compared for occurrence of any non-severe adverse events at each visit of follow-up, from 1 month to 24 months.

Inclusion Criteria: Given informed consent 18 - 75 years of age GCS between 6 and 12 at hospital admission. GCS between 3 and 5 at hospital admission can be enrolled if patient was sedated at the accident scene with previous GCS between 6 and 15. Moderate or severe acute traumatic brain injury All genders Brain CT scan with signs of of acute intraparenchymal hemorrhage and/or contusion Able to receive the first dose of treatment or placebo within 12 hours of brain injury, Exclusion Criteria: Previous use of biperiden History of epilepsy (confirmed by patient chart) History of seizures or use of antiepileptic medication Pregnancy Participation in another clinical trial at the time of randomization History of neoplasia, neurodegenerative diseases; history of stroke, cognitive impairment, benign prostatic hyperplasia, atrioventricular block or any other cardiac arrhythmia, or glaucoma megacolon or mechanical obstruction Homeless patient

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