Early Post-Traumatic Seizures Prevention Trial (E-PTS Trial)

NCT07072624 | Recruiting Phase 4 DMC

• 2 other identifiers: AIIMS/IEC/2024/4889IIRPIG-2023-0001210
• Study Type: interventional
• Target: 1,260
• Locations: 1 country
• Sites: 3

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.

Conditions

Seizures; Traumatic Brain Injuries; Traumatic Brain Injury (TBI) Patients

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

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Clinical Seizure Within 7 Days Post-Traumatic Brain Injury in each of the three treatment groups.

  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).

  7 Days

Secondary Outcomes (4)

• 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

• 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

• 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

• Incremental Cost-Effectiveness Ratio (ICER) of Levetiracetam vs Phenytoin in Preventing Early Post-Traumatic Seizures using Markov chain Monte Carlo simulation.

  1 year

Study Arms (3)

Phenytoin

ACTIVE COMPARATOR

Drug: Phenytoin

Levetiracetam

EXPERIMENTAL

Drug: Levetiracetam

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Phenytoin DRUG

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

Phenytoin

Levetiracetam DRUG

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.

Levetiracetam

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients of severe blunt TBI with GCS score less than 10.
• 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.
• Patients with penetrating injury.

You may not qualify if:

• Females of childbearing age with urine pregnancy test positive.
• Devastating brain injury with expected or confirmed brain death within 48 hours of hospital admission,
• Prehospital use of anticonvulsants
• Development of seizures before enrolment.

Sponsors & Collaborators

• All India Institute of Medical Sciences, Jodhpur: lead
• Indian Council of Medical Research: collaborator
• Post Graduate Institute of Medical Education and Research, Chandigarh: collaborator
• Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow: collaborator

Study Sites (3)

Postgraduate Institute of Medical Education & Research

Chandigarh, Punjab, 160012, India

RECRUITING

AIIMS Jodhpur

Jodhpur, Rajasthan, 342005, India

RECRUITING

Sanjay Gandhi Postgraduate Institute of Medical Sciences

Lucknow, Uttar Pradesh, India

RECRUITING

Related Publications (21)

• Gupta V, Gupta K, Singh G, Kaushal S. An Analytical Study to Correlate Serum Levels of Levetiracetam with Clinical Course in Patients with Epilepsy. J Neurosci Rural Pract. 2016 Dec;7(Suppl 1):S31-S36. doi: 10.4103/0976-3147.196445.

  PMID: 28163500 BACKGROUND

• Kousar S, Wafai ZA, Wani MA, Jan TR, Andrabi KI. Clinical relevance of genetic polymorphism in CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance. Int J Clin Pharmacol Ther. 2015 Jul;53(7):504-16. doi: 10.5414/CP202112.

  PMID: 25943175 BACKGROUND

• Chang WC, Hung SI, Carleton BC, Chung WH. An update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects. Expert Opin Drug Metab Toxicol. 2020 Aug;16(8):723-734. doi: 10.1080/17425255.2020.1780209. Epub 2020 Jul 16.

  PMID: 32510242 BACKGROUND

• Dibbens LM, Hodgson BL, Helbig KL, Oliver KL, Mulley JC, Berkovic SF, Scheffer IE. Rare protein sequence variation in SV2A gene does not affect response to levetiracetam. Epilepsy Res. 2012 Sep;101(3):277-9. doi: 10.1016/j.eplepsyres.2012.04.007. Epub 2012 Apr 30.

  PMID: 22551666 BACKGROUND

• Schivell AE, Mochida S, Kensel-Hammes P, Custer KL, Bajjalieh SM. SV2A and SV2C contain a unique synaptotagmin-binding site. Mol Cell Neurosci. 2005 May;29(1):56-64. doi: 10.1016/j.mcn.2004.12.011.

  PMID: 15866046 BACKGROUND

• Jones KE, Puccio AM, Harshman KJ, Falcione B, Benedict N, Jankowitz BT, Stippler M, Fischer M, Sauber-Schatz EK, Fabio A, Darby JM, Okonkwo DO. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008 Oct;25(4):E3. doi: 10.3171/FOC.2008.25.10.E3.

  PMID: 18828701 BACKGROUND

• Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010 Apr;12(2):165-72. doi: 10.1007/s12028-009-9304-y.

  PMID: 19898966 BACKGROUND

• Jarvie D, Mahmoud SH. Therapeutic Drug Monitoring of Levetiracetam in Select Populations. J Pharm Pharm Sci. 2018;21(1s):149s-176s. doi: 10.18433/jpps30081.

  PMID: 30096051 BACKGROUND

• Cardona AF, Rojas L, Wills B, Bernal L, Ruiz-Patino A, Arrieta O, Hakim EJ, Hakim F, Mejia JA, Useche N, Bermudez S, Carranza H, Vargas C, Otero J, Mayor LC, Ortiz LD, Franco S, Ortiz C, Gil-Gil M, Balana C, Zatarain-Barron ZL. Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma. J Neurooncol. 2018 Jan;136(2):363-371. doi: 10.1007/s11060-017-2660-0. Epub 2017 Nov 25.

  PMID: 29177594 BACKGROUND

• Dikmen SS, Temkin NR, Miller B, Machamer J, Winn HR. Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures. JAMA. 1991 Mar 13;265(10):1271-7.

  PMID: 1995974 BACKGROUND

• Bhullar IS, Johnson D, Paul JP, Kerwin AJ, Tepas JJ 3rd, Frykberg ER. More harm than good: antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery. J Trauma Acute Care Surg. 2014 Jan;76(1):54-60; discussion 60-1. doi: 10.1097/TA.0b013e3182aafd15.

  PMID: 24368357 BACKGROUND

• Young B, Rapp RP, Norton JA, Haack D, Tibbs PA, Bean JR. Failure of prophylactically administered phenytoin to prevent late posttraumatic seizures. J Neurosurg. 1983 Feb;58(2):236-41. doi: 10.3171/jns.1983.58.2.0236.

  PMID: 6848681 BACKGROUND

• Ferguson PL, Smith GM, Wannamaker BB, Thurman DJ, Pickelsimer EE, Selassie AW. A population-based study of risk of epilepsy after hospitalization for traumatic brain injury. Epilepsia. 2010 May;51(5):891-8. doi: 10.1111/j.1528-1167.2009.02384.x. Epub 2009 Oct 20.

  PMID: 19845734 BACKGROUND

• 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.

  PMID: 9414327 BACKGROUND

• Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990 Aug 23;323(8):497-502. doi: 10.1056/NEJM199008233230801.

  PMID: 2115976 BACKGROUND

• Torbic H, Forni AA, Anger KE, Degrado JR, Greenwood BC. Use of antiepileptics for seizure prophylaxis after traumatic brain injury. Am J Health Syst Pharm. 2013 May 1;70(9):759-66. doi: 10.2146/ajhp120203.

  PMID: 23592358 BACKGROUND

• Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.

  PMID: 27654000 BACKGROUND

• Inaba K, Menaker J, Branco BC, Gooch J, Okoye OT, Herrold J, Scalea TM, Dubose J, Demetriades D. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013 Mar;74(3):766-71; discussion 771-3. doi: 10.1097/TA.0b013e3182826e84.

  PMID: 23425733 BACKGROUND

• Agrawal A, Munivenkatappa A, Shukla DP, Menon GR, Alogolu R, Galwankar S, Kumar SS, Momhan PR, Pal R, Rustagi N. Traumatic brain injury related research in India: An overview of published literature. Int J Crit Illn Inj Sci. 2016 Apr-Jun;6(2):65-9. doi: 10.4103/2229-5151.183025.

  PMID: 27308253 BACKGROUND

• Gururaj G. Epidemiology of traumatic brain injuries: Indian scenario. Neurol Res. 2002 Jan;24(1):24-8. doi: 10.1179/016164102101199503.

  PMID: 11783750 BACKGROUND

• Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, Agrawal A, Adeleye AO, Shrime MG, Rubiano AM, Rosenfeld JV, Park KB. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018 Apr 27;130(4):1080-1097. doi: 10.3171/2017.10.JNS17352. Print 2019 Apr 1.

  PMID: 29701556 BACKGROUND

MeSH Terms

Conditions

Seizures; Brain Injuries, Traumatic; Epilepsy, Post-Traumatic

Interventions

Phenytoin; Levetiracetam

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Epilepsy

Intervention Hierarchy (Ancestors)

Hydantoins; Imidazolidines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines

Study Officials

• Dr Apinderpreet Singh Additional Professor, MCh Neurosugery

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

• Dr Kamlesh Bhaisora Additional Professor, MCh Neurosugery

  Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr Jaskaran Singh Gosal Associate Professor, MCh Neurosurgery

CONTACT

91 6283475891; jhsgosal_87@hotmail.com

Dr Shoban Babu Varthya Associate Professor, MD Pharmacology

CONTACT

91 8437726777; drshobanpgimer@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: May 30, 2025
• First Posted: July 18, 2025
• Study Start: July 23, 2025
• Primary Completion (Estimated): March 15, 2027
• Study Completion (Estimated): March 15, 2028
• Last Updated: August 6, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

IN (3)