Seizures, Traumatic Brain Injuries, Traumatic Brain Injury (TBI) Patients
Conditions
Keywords
Post Traumatic Seizures, Early Post Traumatic Seizures, Traumatic Brain Injury, Seizure Prophylaxis, Antiepileptic drugs, Phenytoin, Levetiracetam, Placebo, Genetic polymorphism, CYP2C9, SV2A, Randomized Controlled Trial, Cost-effectiveness, Multicentric Trial
Brief summary
Rationale/gaps in existing knowledge: The prophylaxis for post-traumatic seizures (PTS) remains controversial due to a lack of class I evidence. Investigators plan to conduct a high-quality, prospective, multicentric, randomized study regarding seizure prophylaxis in traumatic brain injury (TBI) with phenytoin, levetiracetam, and the placebo in three respective treatment groups, along with the effect of drug polymorphism on seizure occurrence. Novelty: Literature is scarce regarding the ideal management of early PTS in traumatic brain injury (TBI), a major public health problem. Further, no study has evaluated the effect of genetic polymorphism on seizure occurrence in traumatic brain injury. This Multicentric study will be the first of its kind, not only in India but also globally. Objectives: To evaluate the seizure incidence & efficacy of the respective anti-epileptic drug in each treatment arm. Assessment of clinical & functional outcomes, safety profile, and cost-effectiveness in each group. Effect of genetic polymorphisms on seizure incidence among study participants Methods: A Multicentric prospective randomized placebo-controlled double-blinded clinical trial is planned. After satisfying eligibility criteria and informed consent, TBI patients will be randomly allocated into three arms 'phenytoin arm', 'levetiracetam arm', and 'placebo'. Drug polymorphism will be analyzed in all the patients using quantitative real-time PCR. Expected outcome: This study will provide high-quality evidence in PTS management and will establish the role of prophylactic anti-epileptics in PTS. This study also opens the plethora of undesignated roles of genetic polymorphism in the efficacy and safety of levetiracetam and phenytoin in traumatic brain injury patients.
Interventions
DRUGPhenytoin
The Phenytoin group will be given a loading dose of phenytoin 20 mg/kg intravenously (maximum, 2 gm) at 50 mg per minute and then started on a maintenance dose (5-6 mg/kg/d, rounded to the nearest 100 mg, intravenously administered every 8 hours). The intravenous will be switched to oral once the patient is fit to take it orally or via Ryles tube. The oral dose would be a single 300 mg ER (extended-release) tablet per day. Both IV and/or oral doses of phenytoin will be given only for 1 week after head trauma. Patient= Patients with Traumatic brain injury as per eligibility criteria. Intervention= Phenytoin loading dose IV (20 mg/kg) followed by 100 mg IV TDS till patient accepts orally. Oral dose will be administered as a single 300 mg ER tablet per day. Both IV and oral phenytoin will be given for 1 week after traumatic brain injury and then stopped. Comparator= Matching Placebo
DRUGLevetiracetam
The Levetiracetam group will receive 25-30 mg/kg/d in two divided doses (rounded to 750 mg, administered intravenously every 12 hourly). The intravenous dose will be switched to oral form once the patient is fit to take it orally or via Ryles tube. The oral dose would be two tablets of 750 mg ER (extended-release) levetiracetam daily. Both IV and/or oral doses of levetiracetam will be given only for 1 week after head trauma. Patient= Patients with Traumatic brain injury as per eligibility criteria. Intervention= Levetiracetam IV dosing will be 25-30 mg/Kg/d in 2 divided doses (rounded to 750 mg IV BD) followed by 2 tablets of 750 mg ER once patient fit to take orally or via Ryles tube. Comparator= Matching Placebo.
DRUGPlacebo
The Placebo group will be administered normal saline intravenously of similar amount that of intervention group and matching placebo tablets orally (double dummy) once the patient is fit to take orally. Similar to the intervention group, both IV and oral placebo will be given till 1 week after traumatic brain injury.
Sponsors
Indian Council of Medical Research
Post Graduate Institute of Medical Education and Research, Chandigarh
Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow
All India Institute of Medical Sciences, Jodhpur
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients of severe blunt TBI with GCS score less than 10. 2. Patients with GCS of more than 10 in the presence of computed tomographic imaging findings consistent with brain injury: subarachnoid hemorrhage \[SAH\], subdural hematoma \[SDH\], epidural hematoma \[EDH\], intracerebral hemorrhage \[ICH\], or diffuse axonal injury \[DAI\], depressed skull fracture. 3. Patients with penetrating injury.
Exclusion criteria
1. Females of childbearing age with urine pregnancy test positive. 2. Devastating brain injury with expected or confirmed brain death within 48 hours of hospital admission, 3. Prehospital use of anticonvulsants 4. Development of seizures before enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Seizure Within 7 Days Post-Traumatic Brain Injury in each of the three treatment groups. | 7 Days | A total of 1260 participants experiencing early clinical seizures (defined as any observable seizure activity occurring within 7 days post-trauma), as recorded by treating clinicians, and confirmed through clinical documentation, during the first 7 days of the study intervention period in each group (Phenytoin, Levetiracetam, Placebo). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glasgow Coma Scale scores from baseline at 7 days post-trauma, at 6 months, and 1 year in each treatment group. | 7 Days , 6 Months & 1 year | Title: Functional and Neurological Status Assessed Using Glasgow Coma Scale (GCS). Description: Glasgow Coma Scale (GCS)-a clinical tool used to assess the level of consciousness in traumatic brain injury patients. Scores range from 3 to 15, where higher scores indicate better neurological function. The GCS differentiates between the severities of head injury by score ranges. A GCS of 13-15 indicates a mild head injury, 9-12 moderate and 3-8 severe. Time Frame: GCS: Day 1(Baseline), Day 3, Day 5, and Day 7, at discharge , at 6-month & 1 year follow up. Assessment Method: GCS: Assessed by trained clinical staff daily using standard scoring protocol. |
| Glasgow Outcome Scale scores at hospital discharge, 6-month, and 1-year follow-up in each treatment group. | At discharge, 6 months and 1 year | Title: Functional and Neurological Status Assessed Using Glasgow Outcome Scale (GOS). Description: Glasgow Outcome Scale (GOS) - a global outcome measure of functional recovery post-TBI. Scores range from 1 (death) to 5 (good recovery), where higher scores indicate better outcomes. Time Frame: GOS: At hospital discharge and 6-month follow-up. Assessment method GOS: Assessed at discharge by clinical staff, and at 6 months and at 1 year via telephonic or in-person follow-up |
| Incidence of early clinical seizures in participants, assessed in association with CYP2C9 and SV2A gene polymorphisms, using TaqMan allelic discrimination assay with quantitative real-time PCR (qPCR). | 7 days | Title: Association Between CYP2C9 and SV2A Genetic Polymorphisms and Early Seizure Incidence. Description: Genotyping of CYP2C9 and SV2A polymorphisms will be performed using TaqMan allelic discrimination assay with quantitative real-time PCR. The incidence of early clinical seizures (defined as seizures occurring within 7 days post-trauma) will be compared across different genotype groups. The outcome will be reported as the number and proportion of participants with early seizures by genotype. Time Frame: Within 7 days post-injury Unit of Measure: Number of participants with seizures per genotype group. |
| Incremental Cost-Effectiveness Ratio (ICER) of Levetiracetam vs Phenytoin in Preventing Early Post-Traumatic Seizures using Markov chain Monte Carlo simulation. | 1 year | Description: Cost-effectiveness within the trial will be assessed by calculating the Incremental Cost-Effectiveness Ratio (ICER), defined as the difference in direct medical costs per seizure complication prevented between the phenytoin and levetiracetam groups. Cost data include direct medical cost like drug acquisition, hospital stay, ICU stay, investigations, and seizure-related interventions. Outcome data will include the number of patients with early clinical seizures (within 7 days). Economic evaluation will be performed over a 1-year follow-up period using trial-based data. ICER values will be calculated along with 95% confidence intervals, and sensitivity analyses will be conducted using probabilistic approach. Long-term cost effectiveness will be modelled using Markov chain Monte Carlo simulation. Time Frame: From randomization to 1-year post-injury follow-up. Measure Type: Cost-effectiveness ratio Unit of Measure: INR (₹) per seizure prevented |
Countries
India
Contacts
Primary ContactDr Jaskaran Singh Gosal Associate Professor, MCh Neurosurgery
Backup ContactDr Shoban Babu Varthya Associate Professor, MD Pharmacology
Outcome results
None listed