Short Versus Long-term Levetiracetam in Brain Tumors

Official title

Short Versus Long-term Levetiracetam in Brain Tumors: A Phase 3 Randomized Controlled Trial (LIBRA)

Overview

Levetiracetam is the commonly preferred anti-seizure medicine in patients with brain tumors. This drug has reduced the risk of seizure events occurring but is associated with a risk of side effects such as increased headache, drowsiness, loss of muscle coordination, and psychological challenges in patients. In patients undergoing appropriate treatment for brain tumors and controlled of seizures in the initial few months of levetiracetam, the chance of further seizures is relatively low. The optimal duration to give levetiracetam is not well defined for these patients, and currently as standard treatment levetiracetam is continued for 2-3 years. This study aims to answer this question by comparing patients on a short course of levetiracetam (experimental arm) versus a longer course of levetiracetam (standard arm), with the anticipation that a shorter duration of treatment will not lead to increased seizure episodes.

Detailed description

Patients with prior history of seizure from primary brain tumor in the supratentorial location with controlled seizure on levetiracetam monotherapy for at least six months will be considered for the study. Patients more than 18 years of age with KPS ≥ 50 will be eligible. Patients will be randomized in one of the two arms (standard arm or experimental arm) in a 1:1 ratio and stratified based on seizure type, location, histology, tumor grade, and adjuvant therapy. Randomization will be done by the statistician via computerized software using a permuted block design. In the standard arm, patients will continue on 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 and stopped. 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. The quality-of-life assessment will be done every six months. The primary endpoint is 2-year seizure free survival calculated from the time of randomization.

Patients will continue to receive standard treatment, including adjuvant therapy as standard practice. 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., radio necrosis) or recurrent disease during the study period will be managed according to standard institutional practice without any influence of the study.

An interim analysis is planned for harm or futility to stop the trial when quarter of the expected events have occurred (25% information time), if the observed HR is equal to or greater than the non-inferiority margin (1.47).

At the interim analysis, the one-sided P-value is calculated for testing the hypothesis HR = 1 versus the alternative HR \> 1.73 (the experimental treatment is doing worse than the standard treatment). If the P-value is \<0.0110 at the interim analysis, the trial would stop with the conclusion that non-inferiority cannot be claimed.

The study will be conducted at Tata Memorial Centre and Manipal Academy of Higher Education with a total sample size of 604 patients for a duration of seven years.

Interventions

• Drug Levetiracetam
  Levetiracetam is usually preferred in brain tumor-related epilepsy. Levetiracetam is a second-generation antiepileptic drug that binds to synaptic vesicle glycoprotein SV2A, which interferes with the release of neurotransmitters from the synaptic vesicle and control seizure by multiple mechanisms.

Primary outcome measures

• 2-year seizure free survival [Time frame: 7 year]

Secondary outcome measures (6)

• Overall survival [Time frame: 7 year]
• Progression-free survival [Time frame: 7 year]
• Cost-benefit analysis Cost-benefit analysis [Time frame: 7 year]
• Quality of life core questionnaire [Time frame: 7 year]
• Quality of life brain cancer module [Time frame: 7 year]
• Seizure-free survival between two arms using death as a competing risk [Time frame: 7 years]

Eligibility criteria

Inclusion Criteria: • Age ≥ 18years

• History of seizure
• Histological diagnosis of primary brain tumor
• Supratentorial location of primary tumor
• Controlled on levetiracetam monotherapy for 6 months
• Index surgery within 1 year
• Karnofsky Performance Scale (KPS) ≥ 50

Exclusion criteria

• KPS < 50
• No history of seizure
• Unclear history of seizure episodes in the past
• Use of antiepileptics other than levetiracetam in the previous 6 months
• No histological diagnosis
• Progressive disease
• Brain metastasis
• Altered mental status with deficits in understanding or inability to consent to the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

India · 2 centers

• Manipal Academy of Higher Education — Udupi
• Tata Memorial Centre — Mumbai

Publications

• Pack AM. Epilepsy Overview and Revised Classification of Seizures and Epilepsies. Continuum (Minneap Minn). 2019 Apr;25(2):306-321. doi: 10.1212/CON.0000000000000707. PMID 30921011
• Olafsson 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):627-34. doi: 10.1016/S1474-4422(05)70172-1. PMID 16168931
• Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14. PMID 24730690
• Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshe SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):512-521. doi: 10.1111/epi.13709. Epub 2017 Mar 8. PMID 28276062
• Hildebrand 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):212-5. doi: 10.1212/01.wnl.0000168903.09277.8f. PMID 16043788
• Villemure JG, de Tribolet N. Epilepsy in patients with central nervous system tumors. Curr Opin Neurol. 1996 Dec;9(6):424-8. doi: 10.1097/00019052-199612000-00005. PMID 9007399
• Englot DJ, Chang EF, Vecht CJ. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134:267-85. doi: 10.1016/B978-0-12-802997-8.00016-5. PMID 26948360
• Liigant A, Haldre S, Oun A, Linnamagi U, Saar A, Asser T, Kaasik AE. Seizure disorders in patients with brain tumors. Eur Neurol. 2001;45(1):46-51. doi: 10.1159/000052089. PMID 11150841

Identifiers

NCT: NCT06442748 · 4385

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗