Use of Biperiden for the Prevention of Post-traumatic Epilepsy

Use of Biperiden as a Disease Modifying Agent After Traumatic Brain Injury: a Placebo Controlled, Randomized, Double Blind Study

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.

Study Overview

• Status: Recruiting
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Biperiden Lactate; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 132
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Luiz Mello; Phone Number: 5511-55792033; Email: lemello@unifesp.br

Study Locations

• Brazil
  • Sao Paulo, Brazil
    • Recruiting
    • Federal University of São Paulo
    • Contact: Luiz EM Mello; Phone Number: 55-11-55792033; Email: lemello@unifesp.br
    • Principal Investigator: Luiz EM Mello

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Outcome: Seizure Frequency	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.	during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI
Electroencephalogram Analysis: Presence of Epileptiform Discharges	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.	during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Assessments - Wechsler Adult Intelligence Scale (WAIS) - IV	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.	1, 12 and 24 months after hospital discharge
Quality of Life assessments - Quality of Life after Brain Injury (QOLIBRI)	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).	12 and 24 month after hospital discharge
Neuroimaging techniques - Magnetic Resonance Imaging (MRI) and computed tomography (CT) scan	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.	Measured as soon as possible after TBI, 10 days and 12 months after TBI
Blood sampling biomarkers - Expression of miRNAs	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.	10 days and 1 year after TBI
Blood sampling biomarkers - Expression of the ApoEϵ4 allele	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.	10 days after TBI
Blood sampling biomarkers - Expression of inflammatory cytokines	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.	10 days and 1 year after TBI

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Activity Biomarkers - Presence of high frequency oscillations	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.	during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI
Brain Activity Biomarkers - Presence of cortical spreading depression	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.	during first 10 days after TBI

Collaborators and Investigators

• Sponsor: Federal University of São Paulo
• Collaborators: University of Sao Paulo
• Investigators: Principal Investigator: Rafael Loduca, Federal University of São Paulo

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2018
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): July 31, 2021

Study Registration Dates

• First Submitted: January 12, 2010
• First Submitted That Met QC Criteria: January 12, 2010
• First Posted (Estimate): January 13, 2010

Study Record Updates

• Last Update Posted (Actual): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Traumatic Brain Injury; Biperiden; Post-traumatic Epilepsy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Biperiden; Biperiden lactate
• Other Study ID Numbers: CEP0560/05

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No