Surgeons Trial Of Prophylaxis for Epilepsy in seizure naïve patients with Meningioma: a randomised controlled trial (STOP’EM)

Research question

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? Background

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.

Aims & objectives Primary objective:

•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 Primary economic objective: •Estimate cost effectiveness of prophylactic levetiracetam in seizure-naïve meningioma

Secondary objectives: Determine: •Effect of prophylaxis on time to first seizure & first convulsive seizure •Whether prophylaxis affects quality of life •Whether prophylaxis influences return to driving •Safety of prophylaxis Methods Health technology assessed; 1:1 randomisation: •Intervention: 14 days levetiracetam 500mg bd started one day before surgery

•Comparator: placebo Design: multi-centre, double-blind RCT Setting: 20 UK neurosurgery units Population: seizure-naïve meningioma undergoing surgery Eligibility: Inclusion: •Newly-diagnosed meningioma •Seizure-naïve •For surgery •Age=16-years Exclusion: •Posterior fossa meningioma •Past history of epilepsy/provoked seizures

•Previous cranial surgery •Renal failure Internal pilot: •Stage 1 (at 12 months): establish feasibility of site opening & recruitment

•Stage 2 (at 24 months): corroborate assumptions made about the primary outcome (proportion with seizure at 12 months) Sample size / recruitment:

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.

~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. Timeline (72 months)

•Set-up: 6 months •Pilot: 24 months •Recruitment: 48 months (inclusive of pilot) •Follow-up: 12 months •Data cleaning/analysis: 6 months Impact & dissemination

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.