Clinical trial NCT04945213: Biperiden Trial for Epilepsy Prevention
Official title: Biperiden for Prevention of Epilepsy in Patients With Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Brain Injury Traumatic Moderate
Brain Injury Traumatic Severe
Post Traumatic Epilepsy
Keywords: Brain Injury
Epilepsy
Biperiden
Lead sponsor: Hospital Sirio-Libanes
Sponsor class: OTHER
Collaborators: name: PROADI-SUS
name: Ministry of Health, Brazil
name: University of Sao Paulo
name: Santa Casa de Campo Grande
name: Hospital Sao Rafael
name: Santa Casa de Misericórdia de Sobral
name: Hospital de Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
name: Hospital São Paulo, Universidade Federal de São Paulo
name: Instituto Doutor José Frota
name: Hospital São Vicente de Paulo
First posted: 2021-06-30
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: 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 18 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

Primary outcomes:
measure: Incidence of Post Traumatic Epilepsy (PTE)
timeFrame: 7 days to 24 months
measure: Occurrence of Severe Adverse Events
timeFrame: 24 months
Secondary outcomes:
measure: Electroencephalogram Analyses: Presence of Epileptiform Discharges
timeFrame: 1,3, 6, 9,12,18 and 24 months
measure: Neuropsychological Assessments - semantic memory
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - visual construction
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - information processing speed and attention
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - short term memory
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - visual construction and visuospatial long-term memory
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - verbal long-term memory
timeFrame: 6 and 24 months
measure: Neuropsychological Assessments - executive functions
timeFrame: 6 and 24 months
measure: Health-related quality of life assessment - EQ-5D-3L descriptive system
timeFrame: 3, 6, 12 and 24 months
measure: Health-related quality of life assessment - EQ-VAS self-rated health
timeFrame: 3, 6, 12 and 24 months
measure: Biomarkers - Expression of the ApoEϵ4 allele [ Time Frame: 10 days after TBI ]
timeFrame: Up to 10 days after TBI
measure: Incidence of Post Traumatic Epilepsy (PTE) during the Follow-up
timeFrame: 1,3, 6, 9,12,18 and 24 months
Other outcomes:
measure: Incidence of Mortality
timeFrame: 24 months
measure: Incidence of Non-Severe Adverse Events
timeFrame: 1,3, 6, 9,12,18 and 24 months
Locations:
city: Salvador
country: Brazil
facility: Hospital São Rafael
state: BA
city: Fortaleza
country: Brazil
facility: Instituto Doutor José Frota
state: CE
city: Sobral
country: Brazil
facility: Santa Casa de Misericórdia de Sobral
state: CE
city: Vitória
country: Brazil
facility: Hospital Estadual Urgencia e Emergencia -HEUE
state: ES
city: Campo Grande
country: Brazil
facility: Associação Beneficente Santa Casa de Campo Grande
state: MS
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: RS
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade de Ribeirão Preto
state: SP
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
state: SP
city: São Paulo
country: Brazil
facility: Hospital Sirio-Libanes
city: São Paulo
country: Brazil
facility: Hospital São Paulo, Universidade Federal de São Paulo
Study officials:
affiliation: Hospital Sirio-Libanês
name: Luiz E Mello, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Sirio-Libanês
name: Eliana Garzon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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