A Phase 3 interventional study of Biperiden Lactate and Placebo in Traumatic Brain Injury, sponsored by Federal University of São Paulo. Terminated at 1 site in Brazil. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2023-01-31.
Sponsored by Federal University of São Paulo · Phase 3, Interventional, and Treatment
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.
Treatment with biperiden should 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.
2,113 studies on the registry are indexed under Brain Injuries; 385 are open to participants now.
This study's enrollment of 123 is above the median of 48 across 1,331 interventional studies indexed under Brain Injuries.
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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
Drug: Placebo
5mg IV(in the vein)every 6 hours for 10 days
Also known as: akineton, cinetol
5mg IV(in the vein)every 6 hours for 10 days
Also known as: saline solution
Clinical Outcome: Indidence of post-traumatic epilepsy
The incidence of seizures will be evaluated 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 incidence will be compared between placebo and biperiden-treated patients.
Time frame: 24 months after TBI
Frequency of seizures
The frequency 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. Frequency of seizure will be compared between placebo and biperiden-treated patients.
Time frame: 24 months after TBI
Mortality and adverse effects
The incidence of death and adverse effects will be counted starting immediately after TBI and continuously during the hospitalization period and after hospital discharge during the two year follow up period. Incidence of death and adverse effects will be compared between placebo and biperiden-treated patients.
Time frame: 24 months after TBI
Electroencephalogram Analysis: Presence of Epileptiform Discharges
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.
Time frame: during first 10 days after TBI and 1, 3, 6, 9, 12, 18 and 24 months after TBI
Cognitive Assessments - Wechsler Adult Intelligence Scale (WAIS) - III
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) - III. The WAIS-III 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-III 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.
Time frame: 6, 12 and 24 months after hospital discharge
Quality of Life assessments - European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L), EQ-VAS
The Brazilian version of the EQ-5D-3L and EQ-VAS questioner will be used to assess health-related quality of life (HRQoL), 24 months after TBI. It consists of a questionnaire covering five dimensions of HRQoL (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a visual analog scale (VAS). The descriptive system defines 243 different health states.
Time frame: 24 month after TBI
Blood sampling biomarkers - Expression of miRNAs
Alterations in expression of miRNAs will be assayed in blood samples during treatment with biperiden, or 18 months 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.
Time frame: 10 days or 18 months 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.
Time frame: 10 days or 18 months 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. 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.
Time frame: 10 days after TBI
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.
Time frame: during first 10 days after TBI and 1, 3, 6, 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.
Time frame: during first 10 days after TBI
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Federal University of São Paulo