Title: SPRING - Seizure Prophylaxis IN Glioma
Funder: Chief Scientist Office, Scotland

Abstract: Design: Two arm, multicentre randomised trial of prophylactic anti-epileptic drug (Levetiracetam) versus no anti-epileptic drug (AED) (comparator) in patients with suspected cerebral glioma. Randomly assigned - 1:1 basis Inclusion / Exclusion Criteria Inclusion 1) Suspected cerebral glioma on CT/MRI 2) Age >/= 16 years 3) Karnofsky Performance Status of > 60 4) Able to swallow pills safely 5) Capable of giving informed consent Note – In Chronic Kidney Disease stage 3 (eGFR 30-59 mL/min/1.73m2) (250mg PO twice daily will be given for 2 weeks, then increasing to a maximum of 500mg PO twice daily for a year.. Exclusion 1) Pregnant 2) History of any seizure in the last 10 years 3) Known Severe Chronic Kidney Disease (CKD4 -– eGFR < 30ml/min/1.73m2) 4) Concomitant methotrexate 5) Concomitant AED for other reasons (e.g. pain) 6) Hypersensitivity to Levetiracetam Target Population: Seizure-naïve adults with newly diagnosed suspected glioma where surgery is planned. Health Technologies Being Assessed: Intervention: Pre-operative prophylactic Levetiracetam 500mg PO twice daily for two weeks, then 750mg twice daily thereafter, for one year. (In patients with CKD3, 250mg PO twice daily for 2 weeks, then increasing to a maximum of 500mg PO twice daily for one year). Comparator: No AED. Sample Size: 806 patients. Project timetables including recruitment rate: Project Timetable is a total 65 months (5.42 years) - commencing Apr 2018 • Trial start up (9 months) – Apr 2018 – Dec 2018 • Pilot study (12 months) – Jan 2019 – Dec 2019 • 1 month to review pilot study – Jan 2020 • Recruitment period (24 months) – Feb 2020 – Jan 2022 • Follow-up (12 months) – Feb 2022 – Jan 2023 • Trial close down (6 months) – Feb 2023 – Jul 2023 Recruitment Rate: Estimates from pilot sites suggest that the study would recruit over 989 patients in a 3 year period. Expertise in Team: The core team includes Neurologists, Neurosurgeon, Health Economists, Oncologist, PPI representatives and a clinical trials unit. Please refer to ‘Strengths of Research Team’.

Lay abstract: Gliomas are the most common type of primary brain tumour, with about 6000 new cases each year in the UK. 1 in 5 patients (20%) with a suspected glioma will present with an epileptic seizure & be treated with an anti-epileptic drug (AED). 4 in 5 patients (80%) do not present with seizures. Up to half of these patients will develop epilepsy requiring AED over their lifetime. Seizures can cause anxiety, loss of independence, affect quality of life & sometimes threaten life. AEDs prevent seizures in 50% of patients with epilepsy and reduce frequency and severity of seizures in a further 20-30%. Currently, some doctors prescribe AEDs to patients before neurosurgery for tumours, whilst others do not. We need to find out whether AED is effective and worthwhile, to give the best advice to surgeons & patients in future. Previous studies of AED to prevent seizures in patients with a brain tumour have not shown clear results. However, these studies have included tumour types where the risk of seizures is low and they used older AEDs that may interfere with chemotherapy used in brain tumours and have high risk of side effects. The newer AED, levetiracetam, has fewer side effects & does not interfere with chemotherapy drugs. There is a balance of potential advantages & disadvantages for prescribing prophylactic levetiracetam. What the trial does: Our plan is to approach patients who have newly diagnosed presumed glioma on brain imaging & who have not had a seizure to see if prescribing an AED reduces the risk of seizures. Suitable patients will meet the inclusion criteria Patients will be assigned at random to one of two groups: Group 1 levetiracetam 500mg twice daily for 2 weeks, then increasing to 750mg twice daily thereafter for 1 year. Patients should have a minimum of 2 doses of 500mg prior to surgery. (In those with moderate chronic kidney disease a starting dose of 250mg twice a day for 2 weeks, then increasing to 500mg twice a day thereafter). Group 2 no AED treatment (standard care) The aim of the trial is to see: • if levetiracetam prevents or reduces severity of seizures within the first year • if levetiracetam causes troublesome side effects • if levetiracetam influences progression free survival or overall survival • the cost & health benefits of taking levetiracetam. Patients will follow the normal care pathway specific to their tumour. If patients have a seizure, patients will be asked to contact their usual treating team. A neurologist will review the patient to confirm whether a seizure has occurred. Patients who have a seizure will be asked to complete a seizure diary card & questionnaire about the severity of their seizure. All patients will be asked to complete questionnaires about their symptoms & possible side effects, at entry into the study & every three months for a minimum of one year. There is no need for any additional blood tests or additional hospital visits. 806 patients will be involved from approximately 15 UK centres. Additional centres may be considered depending on recruitment. The trial will be supported locally by a neurosurgeon an oncologist & a neurologist. All patients will be followed up for a minimum of one year. They will be able to continue on levetiracetam at the end of the study or come off it if they wish.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS