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Brain Injury Traumatic ModeratePhase 3BIPERIDENNCT04945213

Biperiden Trial for Epilepsy Prevention

A Phase 3 study testing Biperiden in people with Brain Injury Traumatic Moderate and Brain Injury Traumatic Severe, run by Hospital Sirio-Libanes at 10 sites in Brazil.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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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. Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Biperiden
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
312 participants
Where
10 sitesBrazil
Study dates
10 Jan 2023to 20 Dec 2026
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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,

Who cannot join

  • 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

Trial locations and contacts

10 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Eliana Garzon, MD, PhD contact

+55 (11) 98206-2308

eliana.garzon@hsl.org.br

Maira L Foresti, PhD contact

+ 55(11) 958673803

mairalforesti@gmail.com

10 sites in 1 country

Brazil10 sites, 9 recruiting

  • Associação Beneficente Santa Casa de Campo Grande

    Campo Grande, Mato Grosso do Sul

    Eurico Feltrin, MD, euricofeltrin@hotmail.com

    André Afif, cepec@santacasacg.org.br

    Recruiting

  • Instituto Doutor José Frota

    Fortaleza, Ceará

    Carlos V Melo, carlosviniciusmelo@gmail.com

    Not yet recruiting

  • Hospital São Vicente de Paulo

    Passo Fundo, Rio Grande do Sul

    Active, not recruiting

  • Hospital das Clínicas da Faculdade de Medicina da Universidade de Ribeirão Preto

    Ribeirão Preto, São Paulo

    Guilherme GP Gondim, MD, PhD, podolsky@usp.br

    RODRIGO B CERANTOLA, rcerantola@hcrp.usp.br

    Recruiting

  • Hospital São Rafael

    Salvador, Estado de Bahia

    Humberto Castro, humbertocastrolima@bahiana.edu.br

    Suane MS Mendonca, suane.mendonca@hsr.com.br

    Recruiting

  • Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

    São Paulo, São Paulo

    Almir F Andrade, MD, PhD, almir.andrade@hc.fm.usp.br

    Saul Almeida, MD, saul.silva@hc.fm.usp.br

    Recruiting

  • Hospital Sirio-Libanes

    São Paulo, 01308-000

    Eliana Garzon, PhD, +55 (11) 982062308, eliana.garzon@hsl.org.br

    Carla CG Pinheiro, +55 (11) 3394-4177, carla.cgpinheiro@hsl.org.br

    Recruiting

  • Hospital São Paulo, Universidade Federal de São Paulo

    São Paulo

    Luiz E Mello

    Not yet recruiting

  • Santa Casa de Misericórdia de Sobral

    Sobral, Ceará

    Keven F Ponte, MD, kevenponte@gmail.com

    Eva Cristino, MsC, eva.cristino@sobral.ufc.br

    Recruiting

  • Hospital Estadual Urgencia e Emergencia -HEUE

    Vitória, Espírito Santo

    Rodrigo C Ramos, ensino@heue.aebes.com.br

    Aparecida Taliule, ensino@heue.aebes.com.br

    Not yet recruiting

Other trials in Brazil

About this study

Official title: Biperiden for Prevention of Epilepsy in Patients With Traumatic Brain Injury

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.

Read the 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).

Being tested
Biperiden, Placebo
Keywords
Brain Injury, Epilepsy, Biperiden
Medical subject headings
Epilepsy, Post-Traumatic, Brain Injuries, Epilepsy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BiperidenDrug

    Also called Akineton

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

  • PlaceboOther

    Also called Sterile vehicle (sodium lactate, lactic acid, sodium hydroxide and water for injections)

    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

Study groups in NCT04945213
Study groupRoleWhat they receive
BiperidenExperimentalDrug: Biperiden 5mg of biperiden diluted in 100 ml of 0.9% saline - every 6 hours for 10 consecutive days - IV
Receives: Drug: Biperiden
PlaceboPlacebo comparatorPlacebo 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
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 7 days to 24 months

  2. 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.

    Measured: 24 months

Secondary outcomes (12)

  1. 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.

    Measured: 1,3, 6, 9,12,18 and 24 months

  2. 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.

    Measured: 6 and 24 months

  3. 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.

    Measured: 6 and 24 months

  4. 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.

    Measured: 6 and 24 months

  5. 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.

    Measured: 6 and 24 months

  6. 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.

    Measured: 6 and 24 months

  7. 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.

    Measured: 6 and 24 months

  8. 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.

    Measured: 6 and 24 months

  9. 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.

    Measured: 3, 6, 12 and 24 months

  10. 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.

    Measured: 3, 6, 12 and 24 months

  11. Biomarkers - Expression of the ApoEϵ4 allele [ Time Frame: 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.

    Measured: Up to 10 days after TBI

  12. 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).

    Measured: 1,3, 6, 9,12,18 and 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jun 2021
  2. Study start10 Jan 2023
  3. Primary completion20 Dec 2026 (estimated)
  4. Study completion20 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
312 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04945213
Sponsor's protocol ID
AVAP-NG 1983
Other IDs
39005920810015461
Acronym
BIPERIDEN
Status last verified
Nov 2023
First submitted
25 Jun 2021
Last updated
26 Mar 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

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

    PubMed 24072054

  • 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.

    PubMed 9414327

  • 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.

  • 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.

  • 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.

    PubMed 30121231

  • 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.

    PubMed 29096134

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

    PubMed 15542983

  • 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.

    PubMed 2129092

  • 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.

    PubMed 26485419

  • 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.

    PubMed 30523135

  • 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.

    PubMed 12638104

  • 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.

    PubMed 23538200

  • 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.

    PubMed 33714677

  • 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.

    PubMed 1868801

  • Foresti ML, Garzon E, Pinheiro CCG, Pacheco RL, Riera R, Mello LE. Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial). PLoS One. 2022 Sep 9;17(9):e0273584. doi: 10.1371/journal.pone.0273584. eCollection 2022.

    PubMed 36084082

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Biperiden in people with Brain Injury Traumatic Moderate and Brain Injury Traumatic Severe, run by Hospital Sirio-Libanes at 10 sites in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 26 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Eliana Garzon, MD, PhD (+55 (11) 98206-2308, eliana.garzon@hsl.org.br), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Post Traumatic Epilepsy (PTE) (time frame: 7 days to 24 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04945213, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2024.

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