Biperiden Trial for Epilepsy Prevention

Brain Injury Traumatic Severe Clinical Trial

— BIPERIDEN  

Official title:

Biperiden for Prevention of Epilepsy in Patients With Traumatic Brain Injury

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04945213
• Other study ID #: AVAP-NG 1983
• Secondary ID: 3900592081001546
• Status: Recruiting
• Phase: Phase 3
• Start date: January 10, 2023
• Est. completion date: December 20, 2026

Study information

• Verified date: November 2023
• Source: Hospital Sirio-Libanes
• Contact: Eliana Garzon, MD, PhD
• Phone: +55 (11) 98206-2308
• Email: eliana.garzon[@]hsl.org.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 312
• Est. completion date: December 20, 2026
• Est. primary completion date: December 20, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Brain Injury Traumatic Moderate
• Brain Injury Traumatic Severe
• Epilepsy
• Epilepsy, Post-Traumatic
• Wounds and Injuries

Intervention

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

Other:
• Placebo
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

Locations

Country	Name	City	State
Brazil	Associação Beneficente Santa Casa de Campo Grande	Campo Grande	MS
Brazil	Instituto Doutor José Frota	Fortaleza	CE
Brazil	Hospital São Vicente de Paulo	Passo Fundo	RS
Brazil	Hospital das Clínicas da Faculdade de Medicina da Universidade de Ribeirão Preto	Ribeirão Preto	SP
Brazil	Hospital São Rafael	Salvador	BA
Brazil	Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo	SP
Brazil	Hospital São Paulo, Universidade Federal de São Paulo	São Paulo
Brazil	Hospital Sirio-Libanes	São Paulo
Brazil	Santa Casa de Misericórdia de Sobral	Sobral	CE
Brazil	Hospital Estadual Urgencia e Emergencia -HEUE	Vitória	ES

Sponsors (11)

Lead Sponsor	Collaborator
Hospital Sirio-Libanes	Hospital de Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Hospital São Paulo, Universidade Federal de São Paulo, Hospital Sao Rafael, Hospital São Vicente de Paulo, Instituto Doutor José Frota, Ministry of Health, Brazil, PROADI-SUS, Santa Casa de Campo Grande, Santa Casa de Misericórdia de Sobral, University of Sao Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (14)

Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998 Jan 1;338(1):20-4. doi: 10.1056/NEJM199801013380104. — View Citation

Antoniuk SA. [Non-epileptic disorders in infancy and adolescence]. Medicina (B Aires). 2013;73 Suppl 1:71-6. Spanish. — View Citation

Anvisa. MANUAL PARA NOTIFICAÇÃO DE EVENTOS ADVERSOS E MONITORAMENTO DE SEGURANÇA EM ENSAIOS CLÍNICOS - 1a. edição. 2016. Disponível em: http://portal.anvisa.gov.br/documents/33836/2492465/Manual+para+Notifica%C3%A7%C3%A3o+de+Eventos+Adversos+e+Monitoramento+de+Seguran%C3%A7a+em+Ensaios+Cl%C3%ADnicos+-+1%C2%AA+Edi%C3%A7%C3%A3o/04a68574-8aac-43c9-b0b2-7b7cd80831c4. Acessado em 5 de novembro de 2019.

Aronstam, RS & Patil, P. Muscarinic Receptors: Autonomic Neurons, Encyclopedia of Neuroscience, Academic Press,2009; 1141-1149, ISBN 9780080450469, https://doi.org/10.1016/B978-008045046-9.00692-6.

Benassi SK, Alves JGSM, Guidoreni CG, Massant CG, Queiroz CM, Garrido-Sanabria E, Loduca RDS, Susemihl MA, Paiva WS, de Andrade AF, Teixeira MJ, Andrade JQ, Garzon E, Foresti ML, Mello LE. Two decades of research towards a potential first anti-epileptic drug. Seizure. 2021 Aug;90:99-109. doi: 10.1016/j.seizure.2021.02.031. Epub 2021 Mar 3. — View Citation

Bittencourt S, Ferrazoli E, Valente MF, Romariz S, Janisset NRLL, Macedo CE, Antonio BB, Barros V, Mundim M, Porcionatto M, Aarao MC, Miranda MF, Rodrigues AM, de Almeida AG, Longo BM, Mello LE. Modification of the natural progression of epileptogenesis by means of biperiden in the pilocarpine model of epilepsy. Epilepsy Res. 2017 Dec;138:88-97. doi: 10.1016/j.eplepsyres.2017.10.019. Epub 2017 Oct 29. — View Citation

Brady RD, Casillas-Espinosa PM, Agoston DV, Bertram EH, Kamnaksh A, Semple BD, Shultz SR. Modelling traumatic brain injury and posttraumatic epilepsy in rodents. Neurobiol Dis. 2019 Mar;123:8-19. doi: 10.1016/j.nbd.2018.08.007. Epub 2018 Aug 16. — View Citation

D'Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol. 2004 Dec;17(6):731-5. doi: 10.1097/00019052-200412000-00014. — View Citation

da Silva AM, Vaz AR, Ribeiro I, Melo AR, Nune B, Correia M. Controversies in posttraumatic epilepsy. Acta Neurochir Suppl (Wien). 1990;50:48-51. doi: 10.1007/978-3-7091-9104-0_9. — View Citation

de Almeida CE, de Sousa Filho JL, Dourado JC, Gontijo PA, Dellaretti MA, Costa BS. Traumatic Brain Injury Epidemiology in Brazil. World Neurosurg. 2016 Mar;87:540-7. doi: 10.1016/j.wneu.2015.10.020. Epub 2015 Oct 17. — View Citation

DeVito NJ, Goldacre B. Catalogue of bias: publication bias. BMJ Evid Based Med. 2019 Apr;24(2):53-54. doi: 10.1136/bmjebm-2018-111107. Epub 2018 Dec 6. No abstract available. — View Citation

Englander J, Bushnik T, Duong TT, Cifu DX, Zafonte R, Wright J, Hughes R, Bergman W. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 2003 Mar;84(3):365-73. doi: 10.1053/apmr.2003.50022. — View Citation

Hauser WA, Annegers JF, Kurland LT. Prevalence of epilepsy in Rochester, Minnesota: 1940-1980. Epilepsia. 1991 Jul-Aug;32(4):429-45. doi: 10.1111/j.1528-1157.1991.tb04675.x. — View Citation

Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, Augustovski F, Briggs AH, Mauskopf J, Loder E; CHEERS Task Force. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Value Health. 2013 Mar-Apr;16(2):e1-5. doi: 10.1016/j.jval.2013.02.010. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of Mortality	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,	24 months
Other	Incidence of Non-Severe Adverse Events	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.	1,3, 6, 9,12,18 and 24 months
Primary	Incidence of Post Traumatic Epilepsy (PTE)	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.	7 days to 24 months
Primary	Occurrence of Severe Adverse Events	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.	24 months
Secondary	Electroencephalogram Analyses: Presence of Epileptiform Discharges	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.	1,3, 6, 9,12,18 and 24 months
Secondary	Neuropsychological Assessments - semantic memory	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.	6 and 24 months
Secondary	Neuropsychological Assessments - visual construction	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.	6 and 24 months
Secondary	Neuropsychological Assessments - information processing speed and attention	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.	6 and 24 months
Secondary	Neuropsychological Assessments - short term memory	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.	6 and 24 months
Secondary	Neuropsychological Assessments - visual construction and visuospatial long-term memory	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.	6 and 24 months
Secondary	Neuropsychological Assessments - verbal long-term memory	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.	6 and 24 months
Secondary	Neuropsychological Assessments - executive functions	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.	6 and 24 months
Secondary	Health-related quality of life assessment - EQ-5D-3L descriptive system	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.	3, 6, 12 and 24 months
Secondary	Health-related quality of life assessment - EQ-VAS self-rated health	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.	3, 6, 12 and 24 months
Secondary	Biomarkers - Expression of the ApoE?4 allele [ Time Frame: 10 days after TBI ]	To investigate the expression of the ApoE?4 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 ApoE?4 allele will be correlated with the incidence of seizures in the follow-up assessments after TBI.	Up to 10 days after TBI
Secondary	Incidence of Post Traumatic Epilepsy (PTE) during the Follow-up	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).	1,3, 6, 9,12,18 and 24 months