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Use of Biperiden for the Prevention of Post-traumatic Epilepsy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01048138
Recruitment Status : Recruiting
First Posted : January 13, 2010
Last Update Posted : February 6, 2020
Sponsor:
Collaborator:
University of Sao Paulo
Information provided by (Responsible Party):
Luiz Eugenio Mello, Federal University of São Paulo

Brief Summary:
There is no AED or medication that has been demonstrated to affect the development of post-traumatic epilepsy. Biperiden is a cholinergic antagonist, acting in the muscarinic receptor, that is widely used as an anti Parkinson drug. The investigators data with animal models of epilepsy indicate that anti-muscarinic agents might affect the natural course of the disease in the case of post-traumatic epilepsy.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Drug: Biperiden Lactate Drug: Placebo Phase 3

Detailed Description:
Treatment with biperiden will be initiated in the first 12 hours after trauma as means to avoid the epileptogenic process. The treatment will be repeated every 6 hours for 10 consecutive days. The efficacy of biperiden as an antiepileptogenic drug will be established by analyzing the development of PTE between the biperiden and placebo groups. Several patients' aspects (clinical, electroencephalography, brain imaging, genetic and behavioral data) will be monitored for two year follow-up to unravel the mechanisms by which biperiden exerts its actions on epileptogenesis. The investigators are already at the early stages of patient's recruitment using the available resources.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Use of Biperiden as a Disease Modifying Agent After Traumatic Brain Injury: a Placebo Controlled, Randomized, Double Blind Study
Actual Study Start Date : January 31, 2018
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : July 31, 2020


Arm Intervention/treatment
Experimental: Biperiden Lactate
5mg IV(in the vein)every 6 hours for 10 days
Drug: Biperiden Lactate
5mg IV(in the vein)every 6 hours for 10 days
Other Names:
  • akineton
  • cinetol

Placebo Comparator: Placebo
5mg IV(in the vein)every 6 hours for 10 days
Drug: Placebo
5mg IV(in the vein)every 6 hours for 10 days
Other Name: saline solution




Primary Outcome Measures :
  1. Clinical Outcome: Seizure Frequency [ Time Frame: during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI ]
    The number of seizures will be counted starting immediately after TBI and continuously during the hospitalization period and after hospital discharge during the two year follow up period. Patients and their relatives will be asked to maintain a diary of seizures, and thus record all seizures with detailed descriptions of each event. The recordings will be evaluated in each patient visit. Seizures frequency will be compared between placebo and biperiden-treated patients.

  2. Electroencephalogram Analysis: Presence of Epileptiform Discharges [ Time Frame: during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI ]
    Scalp EEG monitoring will be continuously registered during the first 10 days after TBI. After that, brain activity will be monitored weekly until hospital discharge. Chronically, EEG follow up monitoring will occur 1, 3, 6, 9, 12, 18 and 24 months after TBI. The presence of epileptiform abnormalities (rhythms, spikes, paroxysms, coherence, synchrony and power spectrum of different waveforms, e.g. Alpha, Beta, Theta) will be investigated. The occurrence of epileptiform discharges (and also ictal activity, and changes in the pattern of interictal discharges) will be compared between placebo and biperiden-treated patients.


Secondary Outcome Measures :
  1. Cognitive Assessments - Wechsler Adult Intelligence Scale (WAIS) - IV [ Time Frame: 1, 12 and 24 months after hospital discharge ]
    Cognitive effects of the biperiden therapy will be assessed to demonstrate the efficacy and safety of this medicine in face of its possible cognitive implications. 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 battery of tests will be applied at specific time frames and results will be compared.

  2. Quality of Life assessments - Quality of Life after Brain Injury (QOLIBRI) [ Time Frame: 12 and 24 month after hospital discharge ]
    The Portuguese version of the QOLIBRI (Quality of Life after Brain Injury) questioner will be used to assess health-related quality of life (HRQoL), 12 and 24 months after TBI. This is the first instrument specifically developed to assess quality of life of individuals after TBI. It consists of a questionnaire with 37 items covering six dimensions of HRQoL (cognition, self, daily life and autonomy, social relationships, emotion, physical problems). The responses on each scale are summed to give a total (range form 1 to 5), and then divided by the number of responses to give a scale mean. The QOLIBRI Total score is calculated by summing all the responses, and then dividing by the actual number of responses. The scale means are converted to the 0-100 scale by subtracting 1 from the mean and then multiplying by 25. This produces scale scores which have a lowest possible value of 0 (worst possible quality of life) and a maximum value of 100 (best possible quality of life).

  3. Neuroimaging techniques - Magnetic Resonance Imaging (MRI) and computed tomography (CT) scan [ Time Frame: Measured as soon as possible after TBI, 10 days and 12 months after TBI ]
    Exams including conventional MRI and/or CT scan will be obtained at service admission or as soon as possible following neurosurgeon criteria to confirm evidence of acute intraparenchymal hemorrhage and will be repeated as necessary during hospitalization. Additionally, MRI will be repeated at 10 days after TBI, and also at 1 and 12 months after hospital discharge. MRI lesions will be classified and evaluated regarding their size, location, number, volume and shape, among other factors (T2 flair, DWI, SWI and resting state). Neuroanatomic characteristics evidenced by MRI will be correlated with the incidence of seizures in the follow up assessments after TBI.

  4. Blood sampling biomarkers - Expression of miRNAs [ Time Frame: 10 days and 1 year after TBI ]
    Alterations in expression of miRNAs will be assayed in blood samples during treatment with biperiden and again one year after trauma. Patterns of changes in the miRNA levels will be compared between the groups of patients that developed post-traumatic epilepsy or did not develop epilepsy.

  5. Blood sampling biomarkers - Expression of the ApoEϵ4 allele [ Time Frame: 10 days after TBI ]
    To investigate the expression of the ApoEϵ4 allele in TBI patients, and its correlation with post-traumatic epilepsy development and the biperiden treatment efficacy to prevent epilepsy, RFLP-PCR will be assayed in blood samples of TBI patients. The genotyping reactions will be performed blinded to clinical features. The presence of the ApoEϵ4 allele will be correlated with the incidence of seizures in the follow up assessments after TBI.

  6. Blood sampling biomarkers - Expression of inflammatory cytokines [ Time Frame: 10 days and 1 year after TBI ]
    To verify whether cytokines are differently involved on PTE development, we will perform multi-analyte protein profile in blood plasma samples collected during treatment with biperiden and one year after TBI. Simultaneous measuring of different proteins in plasma will be performed. The concentration of each analyte will be normalized to the total protein concentration and presented as a proportion of specific proteins in picograms (pg) per microgram (μg) of total protein. Patterns of protein expression will be correlated with the incidence of seizures in the follow up assessments after TBI.


Other Outcome Measures:
  1. Brain Activity Biomarkers - Presence of high frequency oscillations [ Time Frame: during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI ]
    Given the requirement of specific adjustments in the EEG recording apparatus (10 KHz sampling rate, high-pass filter above 80 Hz for ripples and 250 Hz for fast ripples), only a subset of patients will be included in this outcome. EEG will be continuously registered during the first 10 days after TBI, weekly until hospital discharge and at specified time frames after TBI. The presence of high frequency oscillations (ripples and fast ripples) will be investigated.

  2. Brain Activity Biomarkers - Presence of cortical spreading depression [ Time Frame: during first 10 days after TBI ]
    Given the requirement of specific adjustments in the EEG recording apparatus (e.g., direct current [DC] recording) to detect cortical spreading depression, a subset of patients will be EEG continuously registered during the first 10 days after trauma with other recording specifications. The presence of cortical spreading depression activity will be investigated.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • between 18 and 75 year of age
  • patients with a diagnosis of severe TBI admitted to an emergency unit within 6 hours of the accident, regardless of the accident
  • brain CT scan with signs of acute intraparenchymatous contusion
  • signed informed consent (possibly by a relative)

Exclusion Criteria:

  • malignant neoplasia and other severe comorbidities
  • neurodegenerative disorders
  • cerebrovascular accident in the previous 6 months
  • record of convulsive seizures or use of anti-epileptic medication
  • pregnancy
  • concomitant use of the other anticholinergic medications
  • presence of any factor that may contraindicate the use of biperiden
  • participation in other clinical trial
  • alcohol intoxication will not lead to exclusion of the subject.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01048138


Contacts
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Contact: Luiz Mello 5511-55792033 lemello@unifesp.br

Locations
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Brazil
Federal University of São Paulo Recruiting
Sao Paulo, Brazil
Contact: Luiz EM Mello    55-11-55792033    lemello@unifesp.br   
Principal Investigator: Luiz EM Mello         
Sponsors and Collaborators
Federal University of São Paulo
University of Sao Paulo
Investigators
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Principal Investigator: Rafael Loduca Federal University of São Paulo

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Responsible Party: Luiz Eugenio Mello, Full Professor, Federal University of São Paulo
ClinicalTrials.gov Identifier: NCT01048138    
Other Study ID Numbers: CEP0560/05
First Posted: January 13, 2010    Key Record Dates
Last Update Posted: February 6, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Luiz Eugenio Mello, Federal University of São Paulo:
Biperiden
Post-traumatic Epilepsy
Traumatic Brain Injury
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Biperiden
Biperiden lactate
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action