Early Post-Traumatic Seizures Prevention Trial (E-PTS Trial)
NCT ID: NCT07072624
Last Updated: 2025-08-06
Study Results
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Basic Information
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RECRUITING
PHASE4
1260 participants
INTERVENTIONAL
2025-07-23
2028-03-15
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
DOUBLE
Study Groups
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Phenytoin
Phenytoin
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
Levetiracetam
Levetiracetam
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.
Placebo
Placebo
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.
Interventions
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Phenytoin
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
Levetiracetam
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.
Placebo
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.
Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
70 Years
ALL
No
Sponsors
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Indian Council of Medical Research
OTHER_GOV
Post Graduate Institute of Medical Education and Research, Chandigarh
OTHER
Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow
UNKNOWN
All India Institute of Medical Sciences, Jodhpur
OTHER_GOV
Responsible Party
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Jaskaran Singh Gosal
Associate Professor
Principal Investigators
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Dr Apinderpreet Singh Additional Professor, MCh Neurosugery
Role: PRINCIPAL_INVESTIGATOR
Post Graduate Institute of Medical Education and Research, Chandigarh
Dr Kamlesh Bhaisora Additional Professor, MCh Neurosugery
Role: PRINCIPAL_INVESTIGATOR
Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow
Locations
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Postgraduate Institute of Medical Education & Research
Chandigarh, Punjab, India
AIIMS Jodhpur
Jodhpur, Rajasthan, India
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Lucknow, Uttar Pradesh, India
Countries
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Central Contacts
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Dr Jaskaran Singh Gosal Associate Professor, MCh Neurosurgery
Role: CONTACT
Dr Shoban Babu Varthya Associate Professor, MD Pharmacology
Role: CONTACT
Facility Contacts
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Dr Apinderpreet Singh Additional Professor, MCh Neurosurgery
Role: primary
Dr Kamlesh bhaisora Additional Professor, MCh Neurosurgery
Role: primary
References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gururaj G. Epidemiology of traumatic brain injuries: Indian scenario. Neurol Res. 2002 Jan;24(1):24-8. doi: 10.1179/016164102101199503.
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.
Other Identifiers
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IIRPIG-2023-0001210
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
AIIMS/IEC/2024/4889
Identifier Type: -
Identifier Source: org_study_id
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