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.
Full Title of Study: “Biperiden for Prevention of Epilepsy in Patients With Traumatic Brain Injury”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Prevention
- Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Study Primary Completion Date: December 20, 2025
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 10 ml of 0.9% saline (treatment group) or saline solution (0,9%) iv, diluted in 10 mg 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 compreehension 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 10 ml of 0.9% saline – every 6 hours for 10 consecutive days – IV
- Other: Placebo
- 1ml of 0.9% saline diluted in 10 ml 0.9% saline – every 6 hours for 10 consecutive days – IV
Arms, Groups and Cohorts
- Experimental: Biperiden
- Drug: Biperiden 5mg of biperiden diluted in 10 ml of 0.9% saline – every 6 hours for 10 consecutive days – IV
- Placebo Comparator: Placebo
- Placebo 1ml of 0.9% saline diluted in 10 ml 0.9% saline – every 6 hours for 10 consecutive days – IV
Clinical Trial Outcome Measures
- Incidence of Post Traumatic Epilepsy (PTE)
- Time Frame: 7 days to 24 months
- 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.
- Ocurrence of Severe Adverse Events
- Time Frame: 24 months
- Proportion of participants that present at least one severe adverse event until 24 months after the traumatic brain injury will be compared betwwen biperiden and placebo groups.
- Electroencephalogram Analyses: Presence of Epileptiform Discharges
- Time Frame: 1,3, 6, 9,12,18 and 24 months
- Electroencephagram (EEG) will be analysed mostly looking for epilepttiform abnormalities and ictal patterns. EEG is going to be recorded at follow-up visits. Data will be compared between placebo and biperiden groups.
- Neuropsychological Assessments
- Time Frame: 6 and 24 months
- Cognitive effects of the biperiden will be assessed to demonstrate the efficacy and safety of this drug. The instruments selected to assess those are tests of the Wechsler Adult Intelligence Scale (WAIS) – IV. The WAIS-IV returns scores on four separate indexes of adult intelligence, the Perceptual Reasoning Index, the Verbal Comprehension Index, the Working Memory Index and the Processing Speed Index. Scores will be calculated on each of the 4 indices and then combined to create a Full-Scale IQ. The WAIS-IV is normed so that 100 is the median score for the adult population (score ranges: 120-129= superior, 110-119= high average, 90-109=average, 80-89= low average, 71-80= borderline intellectual functioning, 50-70= moderate retardation, below 50= severe retardation. The results will be compared between biperiden and placebo groups.
- Quality of Life assessments
- Time Frame: 3, 6, 12 and 24 months
- Quality of life will be evaluated through the portuguese version of EuroQol three-level version (EQ-5D-3L) and EuroQol visual analogue scale (EQ VAS). 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. The EQ VAS 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.
- Biomarkers – Expression of the ApoEϵ4 allele [ Time Frame: 10 days after TBI ]
- Time Frame: Up to 10 days after TBI
- 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.
- Incidence of Post Traumatic Epilepsy (PTE) during the Follow-up
- Time Frame: 1,3, 6, 9,12,18 and 24 months
- 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).
Participating in This Clinical Trial
- Given informed consent – 18 – 75 years of age – Glasgow scale higher than 6 and smaller than 12 at the trauma scene – moderate or severe acute traumatic brain injury – all genders – brain CT scan with signs of acute intraparenchymatous contusion Exclusion Criteria:
- Previous use of biperiden – history of epilepsy (confirmed by patient chart) – History of seizures or use of antiepileptic medication – family history of epilepsy – 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;
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: 75 Years
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Hospital Sirio-Libanes
- Provider of Information About this Clinical Study
- Overall Official(s)
- Luiz E Mello, MD, PhD, Principal Investigator, Hospital Sirio-Libanês
- Eliana Garzon, MD, PhD, Principal Investigator, Hospital Sirio-Libanês
- Overall Contact(s)
- Eliana Garzon, MD, PhD, +55 (11) 98206-2308, firstname.lastname@example.org
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