Study Protocol of Short versus Long-term Levetiracetam in Brain Tumors (LIBRA): A Phase 3 Randomized Controlled Trial

Study Protocol of Short versus Long-term Levetiracetam in Brain Tumors (LIBRA): A Phase 3 Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Study Protocol of Short versus Long-term Levetiracetam in Brain Tumors (LIBRA): A Phase 3 Randomized Controlled Trial Archya Dasgupta, Shakthivel Mani, Abhishek Chatterjee, Sadhana Kannan, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5054111/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Seizures are common in patients with brain tumors, impacting daily life and healthcare burden. In contemporary neuro-oncology practice, levetiracetam is the most commonly prescribed antiepileptic drug (AED). Although the practice is widely variable, levetiracetam is usually used for 2-3 years following surgery as prophylaxis. However, the incidence of seizures post antitumoral treatment is relatively low, and the duration of prophylaxis is not well defined. To address this knowledge gap, the current randomized controlled non-inferiority trial will be conducted comparing a shorter regimen of levetiracetam with the standard long-term schedule. Methods and Analysis: Patients with newly diagnosed primary brain tumors in the supratentorial compartment with a prior history of seizure will be eligible for the study. Adults ( >18 years), within 1 year from surgery, and controlled on levetiracetam monotherapy for 6 months will be randomized in 1:1 ratio to either standard arm (long course: additional 2 years levetiracetam) or experimental arm (short course: tapered of levetiracetam and stopped). Stratification factors include tumor location, seizure type, histology, grade, and adjuvant therapy. The primary endpoint is 2-year seizure-free survival (SFS); secondary endpoints include seizure impact, quality of life, progression-free survival (PFS), and overall survival (OS). Assuming a 2-year SFS rate of 80%, a total of 431 patients (167 events) will be needed to prove the non-inferiority of the experimental arm (non-inferiority margin of 8%, α=0.05, power=80%). Considering an attrition rate of 40% (25% accounting for death and 15% lost to follow-up), the final sample size is 604. Discussion: The trial will provide level 1 evidence on the optimal duration of AED use in primary brain tumors with history of seizures. If short-term AED use is non-inferior, it will reduce drug utilization, lower neurotoxicity, improve quality of life, and optimize resource usage. Ethics and Dissemination : The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. Registration: Registered with CTRI/2024/06/069498, Clinicaltrials.gov: NCT06442748 Oncology Seizures Levetiracetam Brain tumor Antiepileptics Glioma Figures Figure 1 Introduction Seizures are frequently observed in patients with brain tumors, being presenting complaint in 15-30% of patients (1–3). Seizures may develop during treatment (including the immediate post-operative period) and follow-up (4,5). The International League Against Epilepsy (ILAE) clinically defines an epileptic seizure as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (6). The ILAE recognizes tumor-related epilepsies (TRE) as a specific category (7), which include focal awareness seizures (simple partial seizure), focal impaired awareness seizures (complex partial seizures), focal to bilateral tonic-clonic seizures (Secondary Generalized Tonic-Clonic Seizures GTCS), and GTCS (4). The incidence of seizures in brain tumors varies based on the type of tumor, ranging around 85% in low-grade glioma, 69% in anaplastic glioma, 49% in glioblastoma, and more than >80% in glioneural tumors (8,9). Seizures can occur due to several factors, such as tumor location, tumor burden, the growth rate of the tumor, and altered internal milieu in the peritumoral environment (8). Tumors which are located in the frontal lobe, temporal lobe, and eloquent areas of the brain, are more frequently linked with seizures (10). Lower-grade tumors are more likely to have seizure incidence as compared to high-grade tumors, which are rapidly growing tumors (11). Alteration in the neurotransmitter homeostasis, such as the increased release of glutamate from glioma cells, contributes to the glutamatergic cellular pathway, resulting in increased excitability at the synaptic region in the glioma microenvironment (12,13). This is commonly observed in Isocitrate dehydrogenase (IDH) mutant tumors, which have increased production of D-2-Hydroxyglutarate, a glutamate receptor agonist (14,15). In non-glial tumors, information on the mechanism of epileptogenesis is limited; the association of peritumoral edema is commonly related to the incidence of preoperative seizures, specifically in meningiomas (16). The use of antiseizure medications is a common practice in patients with brain tumors and is commonly used as a primary or secondary prophylaxis. The choice of antiseizure medications has changed over the years. Previous generation antiseizure medications such as carbamazepine, phenytoin, and valproic acid are commonly avoided in the first-line setting due to their significant drug interactions and unfavorable toxicity profile (17). Second-generation antiseizure medication such as levetiracetam is usually preferred in brain tumor-related epilepsy. In a recent European Association of Neuro-Oncology (EANO) survey, levetiracetam was the preferred antiepileptic agent in 90% of the respondents (18). The drug is usually well tolerated, has no known drug interactions, and has a favorable toxicity profile (19). Levetiracetam binds to synaptic vesicle glycoprotein SV2A, which interferes with the release of neurotransmitters from the synaptic vesicle. The drug has shown seizure control rates of over 90% in brain tumor patients (20). The drug is considered safe and efficacious while switching over from phenytoin (21), not contraindicated in liver impairment, and is relatively safe in pregnancy (20,22,23). Notably, it is hypothesized that levetiracetam may also contribute to antineoplastic roles by inhibiting epileptogenesis and increasing the activity of chemotherapeutic agents in brain tumors (24). In patients who have undergone antitumoral treatment, the incidence of seizures is relatively low (15-20%), with a doubtful role of AEDS in reducing the incidence of new seizures (8,25). In congruence with the majority of contemporary neuro-oncology practice, levetiracetam is prescribed in our canter for a duration of 2-3 years following surgery as prophylaxis (or at least 2 years from the last seizure episode). The duration of AEDs in preventing seizures is not clearly defined and is routinely extrapolated from non-oncological causes of epilepsy. To address this knowledge gap, we propose a randomized controlled non-inferiority trial comparing a shorter regimen of levetiracetam with the standard long-term schedule. Study Methodology A. Study design/ population This is an open-label, prospective, non-inferiority, interventional, phase 3 randomized controlled trial. Patients will be screened from the neuro-oncology clinic at Tata Memorial Centre, Mumbai. Patients with prior history of seizures with a diagnosis of histologically proven supratentorial brain tumor and no history of seizures on levetiracetam monotherapy for at least six months will be considered eligible for the study. Patients will be assessed for the eligibility criteria below prior to inclusion in the study. Patients will be randomized in one of the two arms (standard arm or experimental arm) in a 1:1 ratio. Randomization will be done via computerized software using a permuted block design. The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. The trial has been registered with the Clinical Trial Registry of India (CTRI/2024/06/069498) and Clinicaltrials.gov (study identifier NCT06442748). Inclusion criteria: 1. Age ≥ 18years 2. History of seizure 3. Histological diagnosis of primary brain tumor 4. Supratentorial location of the primary tumor 5. Controlled on levetiracetam monotherapy for 6 months 6. Index surgery within 1 year 7. Karnofsky Performance Scale (KPS) ≥ 50 Exclusion Criteria 1. Karnofsky Performance Score (KPS) < 50 2. No history of seizure 3. Unclear history of seizure episodes in the past 4. Use of antiepileptics other than levetiracetam in the previous 6 months 5. No histological diagnosis 6. Progressive disease 7. Brain metastasis 8. Altered mental status with deficits in understanding or inability to consent to the study Study intervention After meeting study eligibility, written consent forms will be obtained from all the patients. Patients will be randomized in a 1:1 ratio accounting for the following stratification factors. The following stratification factors will be considered. 1. Seizure type: Focal seizure versus Generalized Tonic-Clonic Seizure versus both 2. Location: Involvement of temporal lobe by tumor or edema (yes versus no) 3. Histology: Diffuse glioma versus meningioma versus others 4. Tumor grade: Grade 4 versus others 5. Adjuvant therapy (radiation/ chemotherapy): yes versus no In the standard arm, patients will continue the same dose and schedule of levetiracetam (typically prescribed in the range of 1000-3000 mg/ day in 2-3 divided doses) for a duration of 2 years. In the experimental arm, levetiracetam will be tapered by 250- 500 mg every week. No additional follow-ups will be required for study purposes, and follow-ups will be done every 3-6 months as per standard practice for the given tumor histology. Neuroimaging will be done 6-12 monthly as per routine clinical practice. A drug diary and seizure diary will be maintained in both arms. The quality-of-life assessment will be done every six months. Study investigators will review the drug and seizure diary during each follow-up visit. The tentative workflow of the study methodology is illustrated in Figure 1 . Patients will continue to receive standard treatment, including adjuvant therapy as standard practice. The study endpoints have been summarized in Table 1. The date of seizure after study accrual will be considered an event for primary endpoint, with the date of randomization considered as the baseline. Radiological evidence of disease progression will be considered as an event for progression-free survival, and the date of death from any cause as an event for overall survival. In case in either arm, the patient develops a seizure episode after stopping levetiracetam will be restarted on levetiracetam monotherapy. If a patient develops a seizure episode while on levetiracetam monotherapy, further add-on antiepileptics will be considered as per standard practice by the responsible physician. Any complications arising from previous treatments (e.g., radionecrosis) or recurrent disease during the study period will be managed according to standard institutional practice without any influence of the study. Sample size calculation: Assuming a 2-year seizure-free survival rate of 80% in the standard arm, the sample size was estimated using a non-inferiority log-rank test. A total of 431 patients (total of 167 events) will be needed to prove the non-inferiority of the experimental arm (non-inferiority margin of 8%, α=0.05, power=80%; HR:1.47). Considering an attrition rate of 40%, with 25% to account for death and 15% lost to follow-up, the final sample size will be 604. We anticipate 150-200 patients to be accrued annually, and with a follow-up of 2 years after the accrual of the last patient, the total study duration is expected to be seven years. Interim analysis: An interim analysis will be done for safety after 25% events (n=42) with stopping the trial if there is a higher incidence of seizures in the experimental arm with a p-value of <0.01. Statistical analysis: Seizure-free survival will be calculated using the Kaplan-Meier method, and differences between the two study arms will be compared using the log-rank test. The date of randomization will be considered as the baseline for survival analysis, the date of seizure will be considered as the event, and a p-value of 0.05 (one-sided) will be considered for statistical analysis. Patients lost to follow-up or dead (in either arm) will be censored for the assessment of seizure-free survival. To conclude non-inferiority, the upper bound of the 90% CI of the hazard ratio resulting from the comparison between the two arms should be less than this prespecified margin of 1.47. All time-to-event outcomes will be calculated using the Kaplan-Meier product-limit method. Univariate and multivariate analyses will be done using the log-rank test and Cox regression, respectively. Toxicity will be documented using Common Toxicity Criteria for Adverse Events (CTCAE) v 5.0 and compared between the groups using the Chi-square test or Fischer exact test as appropriate. Quality of life will be documented using the European Organization for Research and Treatment of Cancer (EORTC) C30 and BN 20 questionnaires. QOL outcomes will be analyzed using longitudinal, repeated measure analyses with mixed effects models with time and treatment interaction, unstructured covariance, and patient-level random effects. Discussion Seizure events can have debilitating effects on individuals. It can impair daily activities, including quality of life, increase the need for healthcare visits, and is associated with neurological morbidity. The chances of seizures recurring after antitumoral treatment is relatively low and will depend on factors such as the extent of resection, tumor location, histological features, and tumor regrowth. Antiepileptics are routinely prescribed as secondary prophylaxis in standard neuro-oncology practice for 2-3 years. Levetiracetam is the commonly preferred AED among neuro-oncologists, with 90% of respondents reporting its use as the first choice in a survey conducted by EANO (18). In our center, levetiracetam is also the preferred monotherapy for management and antiseizure prophylaxis. The efficacy of levetiracetam in reducing seizures is demonstrated at doses of 1000mg, 2000mg, or 3000mg/day in two to three divided doses (26). Levetiracetam has reliable safety but is associated with its own set of toxicity profiles (26). Generalized fatigue and irritability are commonly seen in patients with the use of levetiracetam. Rare side effects include mood disturbances and suicidal tendencies. The current study will randomize patients based on the eligibility criteria into two arms. In the experimental arm, levetiracetam will be tapered by 250-500mg every week and then stopped. In the standard arm, patients would be continued on levetiracetam for another 2 years. The practice regarding the use of antiepileptics in patients with brain tumors is variable, particularly with regard to the duration of use of AEDs. In patients without a history of seizures, the use of AED as prophylaxis is less commonly practiced, with 29% of respondents in the EANO survey reporting the use of AED in seizure-naïve patients (18). The Society for Neuro-Oncology (SNO) and EANO recommended against the use of AEDs in patients without a prior history of seizures (level A evidence) (27). There is a concern about an increased risk of seizures in the post-operative period. The question was addressed by a randomized controlled trial that included 81 patients, and patients without seizure history and undergoing surgery were randomized to 1 week or 6 weeks of levetiracetam prophylaxis (28). The rates of seizure development were low in both arms (1 in each arm), demonstrating the lack of role of AED prophylaxis in the post-operative period. The ongoing phase 3 randomized controlled trial (SPRING) is studying the role of using levetiracetam prophylaxis for 1 year in patients with glioma undergoing surgery and seizure-naïve (29). Another randomized multicentre RCT (STOP ‘EM) is evaluating the role of 2 weeks of levetiracetam prophylaxis in patients with meningioma undergoing surgery without a history of seizures (30). In patients with a history of seizures, AED prophylaxis is considered an essential part of integral management along with appropriate antitumoral therapy, including surgery, radiotherapy, and systemic therapy. With the start of tumor-directed therapy, the chance of seizure relapse is considered to be low, with tumoral activity considered to play a significant role in epileptogenesis (2). According to the EANO survey, 93% of the respondents considered reducing the number of AEDs or complete withdrawal of AED after completion of antitumor treatment (18). Although the exact duration of AED was not studied, precluding understanding of duration of use from diagnosis. It is important to note the duration of antitumor treatment may be highly variable according to the histology or tumor grade. In our study, we have accounted for the variation by incorporating stratification factors such as tumor grade, histology, and use of adjuvant therapy after surgery, which is believed to have important effects on the subsequent risk of seizure relapse. Another important determinant of seizure control is the involvement of temporal lobe, which is associated with relatively poor seizure control, which is another stratification factor in this study. As mentioned earlier, there are no clear data regarding the optimal duration of AED use after the last seizure episode. In general, many clinicians extrapolate the practice of AED use from non-oncological conditions of seizure prophylaxis. To the best of our knowledge, the LIBRA study is the only phase 3 randomized controlled trial investigating the optimal duration of AED prophylaxis. This will generate level 1 evidence guiding contemporary neuro-oncology practice. Also, secondary endpoints of the study will answer critical clinical questions, including cost-benefit analysis, and the impact of long-term use of levetiracetam on quality of life. Interestingly, some interest is laid in the antitumor activity of AEDs, with conflicting results from different studies (27). With a large number of patients to be accrued in the current study (604), we expect to get some insights regarding the effect of levetiracetam on disease control. Conclusion The LIBRA study is a phase 3 randomized controlled trial investing the role of optimal duration of AED prophylaxis in patients with supratentorial brain tumors with a history of seizures. Patients controlled on levetiracetam monotherapy for 6 months will be randomized to either the standard arm (another 2 years of levetiracetam) or the experimental arm (tapered and stopped). The primary endpoint of the study is 2-year seizure-free survival. The study through secondary endpoints would also provide information regarding the impact of AEDs on quality of life and survival outcomes. Declarations Ethics approval and consent to participate The study is being conducted in accordance with ICMR (2017) “National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines, Good Clinical Practice and the principles of the Declaration of Helsinki. The study, including all the study-related documents, has obtained approval from the Ethics Committee prior to the enrolment of participants. The trial has been registered with Clinical Trial Registry of India (CTRI/2024/06/069498) and Clinicaltrials.gov (study identifier NCT06442748). Consent for Publication Not applicable. Conflict Of Interest (COI) All the study investigators declare no conflict of interest in the conduct or outcome of the study. Availability of data and materials Data will be provided upon reasonable request to the principal investigator, following the guidelines by the institutional ethics committee. Funding The study is funded by Brain Tumor Foundation of India. Author contributions: Study concept and design: Archya Dasgupta, Tejpal Gupta, Study conduct and data collection: All authors Statistical analysis: Sadhana Kannan,Archya Dasgupta, Tejpal Gupta, Writing manuscript and approval: All authors Funding acquisition: Archya Dasgupta Study administration: Archya Dasgupta Acknowledgements: We acknowledge the participants and their caregivers for participation in the study. 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TM1-1 Seizure prophylaxis in gliomas (SPRING): a phase III randomised controlled trial comparing prophylactic levetiracetam versus no prophylactic antiepileptic drug in glioma surgery. J Neurol Neurosurg Psychiatry. 2019 Mar 1;90(3):e8–e8. Jenkinson M, Helmy A, Huckey H, Mills S, Grant R, Hughes D, et al. RTID-10. SURGEONS TRIAL OF PROPHYLAXIS FOR EPILEPSY IN SEIZURE NAÏVE PATIENTS WITH MENINGIOMA: A RANDOMIZED CONTROLLED TRIAL (STOP ‘EM). Neuro Oncol. 2020 Nov 9;22(Suppl 2):ii195. Table Table 1: Objectives and endpoints of the study Study Objective To assess seizure-free survival in patients with brain tumors with a history of seizures Study Endpoints Primary Endpoint 2-year seizure-free survival calculated from the time of randomization. Secondary Endpoint 1. Cumulative incidence of seizures impacting awareness in both study arms 2. Two-year seizure-free survival in each stratum. 3.Quality of life assessment 4.Cost-benefit analysis 5.Progression-free survival 6.Overall survival 7.Post hoc analysis per histological category for seizure control Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5054111","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":351159951,"identity":"8d938932-71ad-412f-bddc-2946d7629105","order_by":0,"name":"Archya 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Mumbai","correspondingAuthor":false,"prefix":"","firstName":"Nazia","middleName":"","lastName":"Bano","suffix":""},{"id":351161643,"identity":"b14a0736-24f3-4277-b88f-cd158c6bbd2b","order_by":17,"name":"Farnaz Shaikh","email":"","orcid":"","institution":"Tata Memorial Centre, Homi Bhabha National Institute, Mumbai","correspondingAuthor":false,"prefix":"","firstName":"Farnaz","middleName":"","lastName":"Shaikh","suffix":""},{"id":351161644,"identity":"d34ef879-5b0c-44c2-90b1-72a506af66f4","order_by":18,"name":"Tejpal Gupta","email":"","orcid":"","institution":"Tata Memorial Centre, Homi Bhabha National Institute, Mumbai","correspondingAuthor":false,"prefix":"","firstName":"Tejpal","middleName":"","lastName":"Gupta","suffix":""}],"badges":[],"createdAt":"2024-09-08 20:41:22","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5054111/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5054111/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64228994,"identity":"5d618570-43c3-4a2f-8b3c-b11381797b5c","added_by":"auto","created_at":"2024-09-10 14:30:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":118355,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow of the study\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5054111/v1/e962a9586829b83400b6ae3a.png"},{"id":64228997,"identity":"29215aa2-5c4b-4ca3-ad72-61641d3fbf1c","added_by":"auto","created_at":"2024-09-10 14:30:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":581579,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5054111/v1/c449a0f4-37d6-4d14-aa04-0b2978b36f2f.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eStudy Protocol of Short versus Long-term Levetiracetam in Brain Tumors (LIBRA): A Phase 3 Randomized Controlled Trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction ","content":"\u003cp\u003eSeizures are frequently observed in patients with brain tumors, being presenting complaint in 15-30% of patients\u0026nbsp;(1–3). Seizures may develop during treatment (including the immediate post-operative period) and follow-up\u0026nbsp;(4,5). The International League Against Epilepsy (ILAE) clinically defines an epileptic seizure as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain\u0026nbsp;(6). The ILAE recognizes tumor-related epilepsies (TRE) as a specific category\u0026nbsp;(7), which include focal awareness seizures (simple partial seizure), focal impaired awareness seizures (complex partial seizures), focal to bilateral tonic-clonic seizures (Secondary Generalized Tonic-Clonic Seizures GTCS), and GTCS\u0026nbsp;(4). The incidence of seizures in brain tumors varies based on the type of tumor, ranging around 85% in low-grade glioma, 69% in anaplastic glioma, 49% in glioblastoma, and more than \u0026gt;80% in glioneural tumors\u0026nbsp;(8,9). Seizures can occur due to several factors, such as tumor location, tumor burden, the growth rate of the tumor, and altered internal milieu in the peritumoral environment\u0026nbsp;(8). Tumors which are located in the frontal lobe, temporal lobe, and eloquent areas of the brain, are more frequently linked with seizures\u0026nbsp;(10). Lower-grade tumors are more likely to have seizure incidence as compared to high-grade tumors, which are rapidly growing tumors\u0026nbsp;(11). Alteration in the neurotransmitter homeostasis, such as the increased release of glutamate from glioma cells, contributes to the glutamatergic cellular pathway, resulting in increased excitability at the synaptic region in the glioma microenvironment\u0026nbsp;(12,13). This is commonly observed in Isocitrate dehydrogenase (IDH) mutant tumors, which have increased production of D-2-Hydroxyglutarate, a glutamate receptor agonist\u0026nbsp;(14,15). In non-glial tumors, information on the mechanism of epileptogenesis is limited; the association of peritumoral edema is commonly related to the incidence of preoperative seizures, specifically in meningiomas\u0026nbsp;(16).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The use of antiseizure medications is a common practice in patients with brain tumors and is commonly used as a primary or secondary prophylaxis. The choice of antiseizure medications has changed over the years. Previous generation antiseizure medications such as carbamazepine, phenytoin, and valproic acid are commonly avoided in the first-line setting due to their significant drug interactions and unfavorable toxicity profile\u0026nbsp;(17). Second-generation antiseizure medication such as levetiracetam is usually preferred in brain tumor-related epilepsy. In a recent European Association of Neuro-Oncology (EANO) survey, levetiracetam was the preferred antiepileptic agent in 90% of the respondents\u0026nbsp;(18). The drug is usually well tolerated, has no known drug interactions, and has a favorable toxicity profile\u0026nbsp;(19). Levetiracetam binds to synaptic vesicle glycoprotein SV2A, which interferes with the release of neurotransmitters from the synaptic vesicle. The drug has shown seizure control rates of over 90% in brain tumor patients\u0026nbsp;(20). The drug is considered safe and efficacious while switching over from phenytoin\u0026nbsp;(21), not contraindicated in liver impairment, and is relatively safe in pregnancy\u0026nbsp;(20,22,23). Notably, it is hypothesized that levetiracetam may also contribute to antineoplastic roles by inhibiting epileptogenesis and increasing the activity of chemotherapeutic agents in brain tumors\u0026nbsp;(24). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; In patients who have undergone antitumoral treatment, the incidence of seizures is relatively low (15-20%), with a doubtful role of AEDS in reducing the incidence of new seizures (8,25). In congruence with the majority of contemporary neuro-oncology practice, levetiracetam is prescribed in our canter for a duration of 2-3 years following surgery as prophylaxis (or at least 2 years from the last seizure episode). The duration of AEDs in preventing seizures is not clearly defined and is routinely extrapolated from non-oncological causes of epilepsy. To address this knowledge gap, we propose a randomized controlled non-inferiority trial comparing a shorter regimen of levetiracetam with the standard long-term schedule.\u003c/p\u003e"},{"header":"Study Methodology","content":"\u003cp\u003e\u003cstrong\u003eA. Study design/ population \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is an open-label, prospective, non-inferiority, interventional, phase 3 randomized controlled trial. Patients will be screened from the neuro-oncology clinic at Tata Memorial Centre, Mumbai. Patients with prior history of seizures with a diagnosis of histologically proven supratentorial brain tumor and no history of seizures on levetiracetam monotherapy for at least six months will be considered eligible for the study. Patients will be assessed for the eligibility criteria below prior to inclusion in the study. Patients will be randomized in one of the two arms (standard arm or experimental arm) in a 1:1 ratio. Randomization will be done via computerized software using a permuted block design. The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. The trial has been registered with the Clinical Trial Registry of India (CTRI/2024/06/069498) and Clinicaltrials.gov (study identifier NCT06442748).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Age ≥ 18years \u003c/p\u003e\n\u003cp\u003e2. History of seizure \u003c/p\u003e\n\u003cp\u003e3. Histological diagnosis of primary brain tumor \u003c/p\u003e\n\u003cp\u003e4. Supratentorial location of the primary tumor \u003c/p\u003e\n\u003cp\u003e5. Controlled on levetiracetam monotherapy for 6 months \u003c/p\u003e\n\u003cp\u003e6. Index surgery within 1 year\u003c/p\u003e\n\u003cp\u003e7. Karnofsky Performance Scale (KPS) ≥ 50\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Karnofsky Performance Score (KPS) \u0026lt; 50 \u003c/p\u003e\n\u003cp\u003e2. No history of seizure \u003c/p\u003e\n\u003cp\u003e3. Unclear history of seizure episodes in the past \u003c/p\u003e\n\u003cp\u003e4. Use of antiepileptics other than levetiracetam in the previous 6 months\u003c/p\u003e\n\u003cp\u003e5. No histological diagnosis\u003c/p\u003e\n\u003cp\u003e6. Progressive disease \u003c/p\u003e\n\u003cp\u003e7. Brain metastasis \u003c/p\u003e\n\u003cp\u003e8. Altered mental status with deficits in understanding or inability to consent to the study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter meeting study eligibility, written consent forms will be obtained from all the patients. Patients will be randomized in a 1:1 ratio accounting for the following stratification factors. The following stratification factors will be considered.\u003c/p\u003e\n\u003cp\u003e1. Seizure type: Focal seizure versus Generalized Tonic-Clonic Seizure versus both\u003c/p\u003e\n\u003cp\u003e2. Location: Involvement of temporal lobe by tumor or edema (yes versus no)\u003c/p\u003e\n\u003cp\u003e3. Histology: Diffuse glioma versus meningioma versus others\u003c/p\u003e\n\u003cp\u003e4. Tumor grade: Grade 4 versus others\u003c/p\u003e\n\u003cp\u003e5. Adjuvant therapy (radiation/ chemotherapy): yes versus no\u003c/p\u003e\n\u003cp\u003eIn the standard arm, patients will continue the same dose and schedule of levetiracetam (typically prescribed in the range of 1000-3000 mg/ day in 2-3 divided doses) for a duration of 2 years. In the experimental arm, levetiracetam will be tapered by 250- 500 mg every week. No additional follow-ups will be required for study purposes, and follow-ups will be done every 3-6 months as per standard practice for the given tumor histology. Neuroimaging will be done 6-12 monthly as per routine clinical practice. A drug diary and seizure diary will be maintained in both arms. The quality-of-life assessment will be done every six months. Study investigators will review the drug and seizure diary during each follow-up visit. The tentative workflow of the study methodology is illustrated in \u003cstrong\u003eFigure 1\u003c/strong\u003e. Patients will continue to receive standard treatment, including adjuvant therapy as standard practice. \u003c/p\u003e\n\u003cp\u003eThe study endpoints have been summarized in \u003cstrong\u003eTable 1. \u003c/strong\u003eThe date of seizure after study accrual will be considered an event for primary endpoint, with the date of randomization considered as the baseline. Radiological evidence of disease progression will be considered as an event for progression-free survival, and the date of death from any cause as an event for overall survival. In case in either arm, the patient develops a seizure episode after stopping levetiracetam will be restarted on levetiracetam monotherapy. If a patient develops a seizure episode while on levetiracetam monotherapy, further add-on antiepileptics will be considered as per standard practice by the responsible physician. Any complications arising from previous treatments (e.g., radionecrosis) or recurrent disease during the study period will be managed according to standard institutional practice without any influence of the study. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssuming a 2-year seizure-free survival rate of 80% in the standard arm, the sample size was estimated using a non-inferiority log-rank test. A total of 431 patients (total of 167 events) will be needed to prove the non-inferiority of the experimental arm (non-inferiority margin of 8%, α=0.05, power=80%; HR:1.47). Considering an attrition rate of 40%, with 25% to account for death and 15% lost to follow-up, the final sample size will be 604. We anticipate 150-200 patients to be accrued annually, and with a follow-up of 2 years after the accrual of the last patient, the total study duration is expected to be seven years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn interim analysis will be done for safety after 25% events (n=42) with stopping the trial if there is a higher incidence of seizures in the experimental arm with a p-value of \u0026lt;0.01. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeizure-free survival will be calculated using the Kaplan-Meier method, and differences between the two study arms will be compared using the log-rank test. The date of randomization will be considered as the baseline for survival analysis, the date of seizure will be considered as the event, and a p-value of 0.05 (one-sided) will be considered for statistical analysis. Patients lost to follow-up or dead (in either arm) will be censored for the assessment of seizure-free survival. To conclude non-inferiority, the upper bound of the 90% CI of the hazard ratio resulting from the comparison between the two arms should be less than this prespecified margin of 1.47. All time-to-event outcomes will be calculated using the Kaplan-Meier product-limit method. Univariate and multivariate analyses will be done using the log-rank test and Cox regression, respectively. Toxicity will be documented using Common Toxicity Criteria for Adverse Events (CTCAE) v 5.0 and compared between the groups using the Chi-square test or Fischer exact test as appropriate. Quality of life will be documented using the European Organization for Research and Treatment of Cancer (EORTC) C30 and BN 20 questionnaires. QOL outcomes will be analyzed using longitudinal, repeated measure analyses with mixed effects models with time and treatment interaction, unstructured covariance, and patient-level random effects.\u003c/p\u003e"},{"header":"Discussion ","content":"\n\u003cp\u003eSeizure events can have debilitating effects on individuals. It can impair daily activities, including quality of life, increase the need for healthcare visits, and is associated with neurological morbidity. The chances of seizures recurring after antitumoral treatment is relatively low and will depend on factors such as the extent of resection, tumor location, histological features, and tumor regrowth. Antiepileptics are routinely prescribed as secondary prophylaxis in standard neuro-oncology practice for 2-3 years. Levetiracetam is the commonly preferred AED among neuro-oncologists, with 90% of respondents reporting its use as the first choice in a survey conducted by EANO (18). In our center, levetiracetam is also the preferred monotherapy for management and antiseizure prophylaxis. The efficacy of levetiracetam in reducing seizures is demonstrated at doses of 1000mg, 2000mg, or 3000mg/day in two to three divided doses (26). Levetiracetam has reliable safety but is associated with its own set of toxicity profiles (26). Generalized fatigue and irritability are commonly seen in patients with the use of levetiracetam. Rare side effects include mood disturbances and suicidal tendencies. The current study will randomize patients based on the eligibility criteria into two arms. In the experimental arm, levetiracetam will be tapered by 250-500mg every week and then stopped. In the standard arm, patients would be continued on levetiracetam for another 2 years. \u003c/p\u003e\n\u003cp\u003eThe practice regarding the use of antiepileptics in patients with brain tumors is variable, particularly with regard to the duration of use of AEDs. In patients without a history of seizures, the use of AED as prophylaxis is less commonly practiced, with 29% of respondents in the EANO survey reporting the use of AED in seizure-na\u0026iuml;ve patients (18). The Society for Neuro-Oncology (SNO) and EANO recommended against the use of AEDs in patients without a prior history of seizures (level A evidence) (27). There is a concern about an increased risk of seizures in the post-operative period. The question was addressed by a randomized controlled trial that included 81 patients, and patients without seizure history and undergoing surgery were randomized to 1 week or 6 weeks of levetiracetam prophylaxis (28). The rates of seizure development were low in both arms (1 in each arm), demonstrating the lack of role of AED prophylaxis in the post-operative period. The ongoing phase 3 randomized controlled trial (SPRING) is studying the role of using levetiracetam prophylaxis for 1 year in patients with glioma undergoing surgery and seizure-na\u0026iuml;ve (29). Another randomized multicentre RCT (STOP \u0026lsquo;EM) is evaluating the role of 2 weeks of levetiracetam prophylaxis in patients with meningioma undergoing surgery without a history of seizures (30). \u003c/p\u003e\n\u003cp\u003eIn patients with a history of seizures, AED prophylaxis is considered an essential part of integral management along with appropriate antitumoral therapy, including surgery, radiotherapy, and systemic therapy. With the start of tumor-directed therapy, the chance of seizure relapse is considered to be low, with tumoral activity considered to play a significant role in epileptogenesis (2). According to the EANO survey, 93% of the respondents considered reducing the number of AEDs or complete withdrawal of AED after completion of antitumor treatment (18). Although the exact duration of AED was not studied, precluding understanding of duration of use from diagnosis. It is important to note the duration of antitumor treatment may be highly variable according to the histology or tumor grade. In our study, we have accounted for the variation by incorporating stratification factors such as tumor grade, histology, and use of adjuvant therapy after surgery, which is believed to have important effects on the subsequent risk of seizure relapse. Another important determinant of seizure control is the involvement of temporal lobe, which is associated with relatively poor seizure control, which is another stratification factor in this study. As mentioned earlier, there are no clear data regarding the optimal duration of AED use after the last seizure episode. In general, many clinicians extrapolate the practice of AED use from non-oncological conditions of seizure prophylaxis. \u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, the LIBRA study is the only phase 3 randomized controlled trial investigating the optimal duration of AED prophylaxis. This will generate level 1 evidence guiding contemporary neuro-oncology practice. Also, secondary endpoints of the study will answer critical clinical questions, including cost-benefit analysis, and the impact of long-term use of levetiracetam on quality of life. Interestingly, some interest is laid in the antitumor activity of AEDs, with conflicting results from different studies (27). With a large number of patients to be accrued in the current study (604), we expect to get some insights regarding the effect of levetiracetam on disease control. \u003c/p\u003e"},{"header":"Conclusion ","content":"\u003cp\u003eThe LIBRA study is a phase 3 randomized controlled trial investing the role of optimal duration of AED prophylaxis in patients with supratentorial brain tumors with a history of seizures. Patients controlled on levetiracetam monotherapy for 6 months will be randomized to either the standard arm (another 2 years of levetiracetam) or the experimental arm (tapered and stopped). The primary endpoint of the study is 2-year seizure-free survival. The study through secondary endpoints would also provide information regarding the impact of AEDs on quality of life and survival outcomes.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is being conducted in accordance with ICMR (2017) “National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines, Good Clinical Practice and the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eThe study, including all the study-related documents, has obtained approval from the Ethics Committee prior to the enrolment of participants.\u0026nbsp;The trial has been registered with Clinical Trial Registry of India (CTRI/2024/06/069498) and Clinicaltrials.gov (study identifier\u0026nbsp;NCT06442748).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict Of Interest (COI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the study investigators declare no conflict of interest in the conduct or outcome of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be provided upon reasonable request to the principal investigator, following the guidelines by the institutional ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is funded by Brain Tumor Foundation of India.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy concept and design:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta, Tejpal Gupta,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy conduct and data collection:\u0026nbsp;\u003c/strong\u003eAll authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u0026nbsp;\u003c/strong\u003eSadhana Kannan,Archya Dasgupta, Tejpal Gupta,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting manuscript and approval:\u0026nbsp;\u003c/strong\u003eAll authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding acquisition:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy administration:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the participants and their caregivers for participation in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003evan Breemen MSM, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 2007 May;6(5):421\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003evan der Meer PB, Taphoorn MJB, Koekkoek JAF. Management of epilepsy in brain tumor patients. Curr Opin Oncol. 2022 Nov 1;34(6):685\u0026ndash;90.\u003c/li\u003e\n \u003cli\u003eAvila EK, Tobochnik S, Inati SK, Koekkoek JAF, McKhann GM, Riviello JJ, et al. Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management. Neuro Oncol. 2023 Sep 12;noad154.\u003c/li\u003e\n \u003cli\u003ePack AM. Epilepsy Overview and Revised Classification of Seizures and Epilepsies. Continuum (Minneap Minn). 2019 Apr;25(2):306\u0026ndash;21.\u003c/li\u003e\n \u003cli\u003eOlafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 2005 Oct;4(10):627\u0026ndash;34.\u003c/li\u003e\n \u003cli\u003eFisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia [Internet]. 2014 [cited 2023 May 28];55(4):475\u0026ndash;82. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.12550\u003c/li\u003e\n \u003cli\u003eScheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):512\u0026ndash;21.\u003c/li\u003e\n \u003cli\u003eHildebrand J, Lecaille C, Perennes J, Delattre JY. Epileptic seizures during follow-up of patients treated for primary brain tumors. Neurology. 2005 Jul 26;65(2):212\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eVillemure JG, de Tribolet N. Epilepsy in patients with central nervous system tumors. Curr Opin Neurol. 1996 Dec;9(6):424\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eEnglot DJ, Chang EF, Vecht CJ. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134:267\u0026ndash;85.\u003c/li\u003e\n \u003cli\u003eXie M, Wang X, Duan Z, Luan G. Low-grade epilepsy-associated neuroepithelial tumors: Tumor spectrum and diagnosis based on genetic alterations. Front Neurosci. 2022;16:1071314.\u003c/li\u003e\n \u003cli\u003eHwang SL, Lin CL, Lee KS, Lieu AS, Kuo TH, Chang CZ, et al. Factors influencing seizures in adult patients with supratentorial astrocytic tumors. Acta Neurochir (Wien). 2004 Jun;146(6):589-594: discussion 594.\u003c/li\u003e\n \u003cli\u003eYuen TI, Morokoff AP, Bjorksten A, D\u0026rsquo;Abaco G, Paradiso L, Finch S, et al. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology. 2012 Aug 28;79(9):883\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eAndronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR, et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med. 2012 Jan 11;4(116):116ra4.\u003c/li\u003e\n \u003cli\u003eNagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, et al. Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. Neuro Oncol. 2016 Nov;18(11):1559\u0026ndash;68.\u003c/li\u003e\n \u003cli\u003eEnglot DJ, Magill ST, Han SJ, Chang EF, Berger MS, McDermott MW. Seizures in supratentorial meningioma: a systematic review and meta-analysis. J Neurosurg. 2016 Jun;124(6):1552\u0026ndash;61.\u003c/li\u003e\n \u003cli\u003eYap KYL, Chui WK, Chan A. Drug interactions between chemotherapeutic regimens and antiepileptics. Clin Ther. 2008 Aug;30(8):1385\u0026ndash;407.\u003c/li\u003e\n \u003cli\u003evan der Meer PB, Dirven L, van den Bent MJ, Preusser M, Taphoorn MJB, Rud\u0026aacute; R, et al. Prescription preferences of antiepileptic drugs in brain tumor patients: An international survey among EANO members. Neurooncol Pract. 2022 Apr;9(2):105\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eMaschio M. Brain tumor-related epilepsy. Curr Neuropharmacol. 2012 Jun;10(2):124\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eRosati A, Buttolo L, Stefini R, Todeschini A, Cenzato M, Padovani A. Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch Neurol. 2010 Mar;67(3):343\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eLim DA, Tarapore P, Chang E, Burt M, Chakalian L, Barbaro N, et al. Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol. 2009 Jul;93(3):349\u0026ndash;54.\u003c/li\u003e\n \u003cli\u003eChamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020 Apr 11;395(10231):1217\u0026ndash;24.\u003c/li\u003e\n \u003cli\u003eRoberti R, Rocca M, Iannone LF, Gasparini S, Pascarella A, Neri S, et al. Status epilepticus in pregnancy: a literature review and a protocol proposal. Expert Rev Neurother. 2022 Apr;22(4):301\u0026ndash;12.\u003c/li\u003e\n \u003cli\u003eCucchiara F, Pasqualetti F, Giorgi FS, Danesi R, Bocci G. Epileptogenesis and oncogenesis: An antineoplastic role for antiepileptic drugs in brain tumours? Pharmacological Research [Internet]. 2020 Jun 1 [cited 2023 Oct 8];156:104786. Available from: https://www.sciencedirect.com/science/article/pii/S1043661820302851\u003c/li\u003e\n \u003cli\u003eLiigant A, Haldre S, Oun A, Linnam\u0026auml;gi U, Saar A, Asser T, et al. Seizure disorders in patients with brain tumors. Eur Neurol. 2001;45(1):46\u0026ndash;51.\u003c/li\u003e\n \u003cli\u003eHoward P, Remi J, Remi C, Charlesworth S, Whalley H, Bhatia R, et al. Levetiracetam. J Pain Symptom Manage. 2018 Oct;56(4):645\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eWalbert T, Harrison RA, Schiff D, Avila EK, Chen M, Kandula P, et al. SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neuro Oncol. 2021 Nov 2;23(11):1835\u0026ndash;44.\u003c/li\u003e\n \u003cli\u003eRahman M, Eisenschenk S, Melnick K, Wang Y, Heaton S, Ghiaseddin A, et al. Duration of Prophylactic Levetiracetam After Surgery for Brain Tumor: A Prospective Randomized Trial. Neurosurgery. 2023 Jan 1;92(1):68\u0026ndash;74.\u003c/li\u003e\n \u003cli\u003eJenkinson MD, Watts C, Marson AG, Hill R, Murray K, Vale L, et al. TM1-1 Seizure prophylaxis in gliomas (SPRING): a phase III randomised controlled trial comparing prophylactic levetiracetam versus no prophylactic antiepileptic drug in glioma surgery. J Neurol Neurosurg Psychiatry. 2019 Mar 1;90(3):e8\u0026ndash;e8.\u003c/li\u003e\n \u003cli\u003eJenkinson M, Helmy A, Huckey H, Mills S, Grant R, Hughes D, et al. RTID-10. SURGEONS TRIAL OF PROPHYLAXIS FOR EPILEPSY IN SEIZURE NA\u0026Iuml;VE PATIENTS WITH MENINGIOMA: A RANDOMIZED CONTROLLED TRIAL (STOP \u0026lsquo;EM). Neuro Oncol. 2020 Nov 9;22(Suppl 2):ii195.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Objectives and endpoints of the study\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Objective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTo assess seizure-free survival in patients with brain tumors with a history of seizures\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Endpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2-year seizure-free survival calculated from the time of randomization.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary Endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1. Cumulative incidence of seizures impacting awareness in both study arms\u003c/p\u003e\n \u003cp\u003e2. Two-year seizure-free survival in each stratum.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.Quality of life assessment\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.Cost-benefit analysis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.Progression-free survival\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.Overall survival\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.Post hoc analysis per histological category for seizure control\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Tata Memorial Hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Seizures, Levetiracetam, Brain tumor, Antiepileptics, Glioma","lastPublishedDoi":"10.21203/rs.3.rs-5054111/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5054111/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Seizures are common in patients with brain tumors, impacting daily life and healthcare burden. In contemporary neuro-oncology practice, levetiracetam is the most commonly prescribed antiepileptic drug (AED). Although the practice is widely variable, levetiracetam is usually used for 2-3 years following surgery as prophylaxis. However, the incidence of seizures post antitumoral treatment is relatively low, and the duration of prophylaxis is not well defined. To address this knowledge gap, the current randomized controlled non-inferiority trial will be conducted comparing a shorter regimen of levetiracetam with the standard long-term schedule.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and Analysis:\u003c/strong\u003e Patients with newly diagnosed primary brain tumors in the supratentorial compartment with a prior history of seizure will be eligible for the study. Adults ( \u0026gt;18 years), within 1 year from surgery, and controlled on levetiracetam monotherapy for 6 months will be randomized in 1:1 ratio to either standard arm (long course: additional 2 years levetiracetam) or experimental arm (short course: tapered of levetiracetam and stopped). Stratification factors include tumor location, seizure type, histology, grade, and adjuvant therapy. The primary endpoint is 2-year seizure-free survival (SFS); secondary endpoints include seizure impact, quality of life, progression-free survival (PFS), and overall survival (OS). Assuming a 2-year SFS rate of 80%, a total of 431 patients (167 events) will be needed to prove the non-inferiority of the experimental arm (non-inferiority margin of 8%, α=0.05, power=80%). Considering an attrition rate of 40% (25% accounting for death and 15% lost to follow-up), the final sample size is 604.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e The trial will provide level 1 evidence on the optimal duration of AED use in primary brain tumors with history of seizures. If short-term AED use is non-inferior, it will reduce drug utilization, lower neurotoxicity, improve quality of life, and optimize resource usage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Dissemination\u003c/strong\u003e: The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration:\u003c/strong\u003e Registered with CTRI/2024/06/069498, Clinicaltrials.gov: NCT06442748\u003c/p\u003e","manuscriptTitle":"Study Protocol of Short versus Long-term Levetiracetam in Brain Tumors (LIBRA): A Phase 3 Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-10 14:30:28","doi":"10.21203/rs.3.rs-5054111/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7a2f2cd-607c-4606-84d4-3c5ed7af4112","owner":[],"postedDate":"September 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":37287073,"name":"Oncology"}],"tags":[],"updatedAt":"2024-09-10T14:30:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-10 14:30:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5054111","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5054111","identity":"rs-5054111","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}