Title: Surgeons Trial Of Prophylaxis for Epilepsy in seizure naïve patients with Meningioma: a randomised controlled trial (STOP’EM)
Funder: Department of Health and Social Care

Abstract: Context:_x000D_ This is a study aiming to help adults diagnosed with a meningioma brain tumour that needs surgical removal and who have not had a seizure beforehand. We want to know whether a short course of an anti-epileptic drug (AED) started 1 day before surgery will prevent seizures happening after surgery._x000D_ _x000D_ Meningiomas are the most common type of primary brain tumour. They grow from the lining of the brain. Most meningiomas are non-malignant, can be removed with surgery and do not regrow. In the UK each year, about 1600 people with a meningioma have surgery. Approximately 70% of people with meningiomas do not present with epileptic seizures, but following surgical removal around 12% will have a seizure within the first 12 months. Seizures affect people’s quality of life in many ways and lead to uncertainty about the future. They cause anxiety and social stigma, affect activities of daily living, cause a loss of independence, including loss of driving license, and can threaten life._x000D_ _x000D_ In patients who have never had a seizure, neurosurgeons don’t know whether giving an AED before surgery (known as prophylaxis) will prevent seizures. In the UK and internationally, some neurosurgeons use prophylaxis and others do not. Previous studies have not shown conclusive results and were done using older drugs with worse side effects._x000D_ _x000D_ What this study does:_x000D_ This study will compare a newer, but well-established anti-epileptic drug called levetiracetam, to a placebo (a capsule that looks the same but has no active drug in it), and will determine:_x000D_ 1) Whether starting levetiracetam shortly before surgery (as a preventative measure) reduces the chance of developing a seizure in the first 12 months after surgery_x000D_ 2) Whether starting levetiracetam shortly before surgery (as a preventative measure) allows more people to resume driving at 6 and 12 months after surgery_x000D_ 3) The quality of life in patients undergoing surgery for meningioma_x000D_ 4) Whether the prophylactic use of levetiracetam is cost effective_x000D_ _x000D_ Where this study will open:_x000D_ 20 neurosurgery units in the UK._x000D_ _x000D_ Who can take part:_x000D_ Adults who have a meningioma that needs surgical removal and who have not had a seizure beforehand, can take part. We will recruit 1004 patients._x000D_ _x000D_ How will the trial work:_x000D_ Participants will be assigned at random to one of two groups:_x000D_ Group 1: levetiracetam (500mg morning & night: started 1 day before surgery & continued for 14 days)_x000D_ Group 2: placebo (started 1 day before surgery & continued for 14 days)_x000D_ _x000D_ Participants will follow the normal care pathway and will be seen in clinic after surgery at 2-6 weeks, 3 and 12 months, as well as having a telephone consultation at 6 & 9 months. Participants will complete quality of life questionnaires before surgery and at 12 months. Participants will be followed up for a total of 12 months.

Lay abstract: Research question_x000D_ In patients with newly-diagnosed meningioma who have never had a seizure and are undergoing surgical resection, does a 14 day course of prophylactic levetiracetam started one day before surgery, reduce the risk of developing seizures?_x000D_ _x000D_ Background_x000D_ Meningioma is the commonest primary brain tumour. 1600 patients/year have surgery in the UK. At diagnosis, 70% of patients will not have had seizures, but ~12% of the seizure-naïve patients will have a seizure within 12 months of surgery. Seizures impact quality of life and can be life-threatening. Side effects from anti-epileptic drugs (AED) also affect quality of life. Neurosurgeons administer prophylactic AEDs to prevent seizures despite a lack of evidence to support this. A meta-analysis of RCTs in brain tumours suggests that older AED may prevent seizures in the first week after surgery but not thereafter. There are no studies assessing newer AEDs in the prophylactic setting._x000D_ _x000D_ Aims & objectives_x000D_ Primary objective:_x000D_ •Determine whether 2 weeks prophylactic levetiracetam reduces the risk of developing seizures within 12 months of surgery for newly-diagnosed seizure naïve meningioma compared to placebo_x000D_ _x000D_ Primary economic objective:_x000D_ •Estimate cost effectiveness of prophylactic levetiracetam in seizure-naïve meningioma_x000D_ _x000D_ Secondary objectives: _x000D_ Determine:_x000D_ •Effect of prophylaxis on time to first seizure & first convulsive seizure_x000D_ •Whether prophylaxis affects quality of life_x000D_ •Whether prophylaxis influences return to driving_x000D_ •Safety of prophylaxis_x000D_ _x000D_ Methods_x000D_ Health technology assessed; 1:1 randomisation:_x000D_ •Intervention: 14 days levetiracetam 500mg bd started one day before surgery_x000D_ •Comparator: placebo_x000D_ _x000D_ Design: multi-centre, double-blind RCT_x000D_ _x000D_ Setting: 20 UK neurosurgery units_x000D_ _x000D_ Population: seizure-naïve meningioma undergoing surgery_x000D_ _x000D_ Eligibility:_x000D_ Inclusion:_x000D_ •Newly-diagnosed meningioma_x000D_ •Seizure-naïve_x000D_ •For surgery_x000D_ •Age=16 years_x000D_ _x000D_ Exclusion:_x000D_ •Posterior fossa meningioma_x000D_ •Past history of epilepsy/provoked seizures_x000D_ •Previous cranial surgery_x000D_ •Renal failure_x000D_ _x000D_ Internal pilot:_x000D_ •Stage 1 (at 12 months): establish feasibility of site opening & recruitment_x000D_ •Stage 2 (at 24 months): corroborate assumptions made about the primary outcome (proportion with seizure at 12 months)_x000D_ _x000D_ Sample size / recruitment:_x000D_ Seizure rate at 12 months is 12.3%. A 50% reduction is clinically beneficial. A two group ?² test with a 5% two-sided significance level will have 90% power to detect the difference between a Group 1 proportion of 0.12 and a Group 2 proportion of 0.06 when the sample size in each group is 477. Allowing for 5% dropout, 1004 patients will be recruited._x000D_ ~1600 operated meningioma per year; 85-90% supratentorial (n=1360); 70% are seizure naïve (n=952). Assuming a conservative recruitment rate of 1.2 per month and site, a 4 year recruitment period is needed to allow staggered site opening and a conservative estimate of eligibility/consent._x000D_ _x000D_ Timeline (72 months)_x000D_ •Set-up: 6 months_x000D_ •Pilot: 24 months_x000D_ •Recruitment: 48 months (inclusive of pilot)_x000D_ •Follow-up: 12 months_x000D_ •Data cleaning/analysis: 6 months_x000D_ _x000D_ Impact & dissemination_x000D_ Study set up, promotion, recruitment and results by study team & charities. Meningioma is commonest brain tumour and the study will lead to guidelines for seizure prophylaxis that will inform national and international neurosurgery practice. UK impact to be measured through the neurosurgery GIRFT (Getting It Right First Time) programme.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;NEUROLOGICAL