Background 50-80% of all glioma patients will have seizures. Guidelines recommend against prophylactic anti-seizure medication, but levetiracetam is frequently prescribed. Our aim was to determine the effectiveness of 12-months prophylactic levetiracetam at reducing seizure risk.

Methods Seizure-naïve patients undergoing glioma surgery were randomised (1:1) to 12-months levetiracetam or no prophylaxis and followed until death or maximum 18-months. The primary outcome was one-year risk of first seizure. Patients who died within 12-months of randomisation without experiencing a seizure were excluded from the primary outcome analysis. Target accrual was 804 participants. The trial was registered (ISRCTN 49474281 and EudraCT 2018-001312-30).

Results Between Oct 10, 2019 and Aug 30, 2022, 96 patients, from 24 to 79 years of age, were randomised to levetiracetam (n=49) or no prophylaxis (n=47). The trial closed early due to slow accrual and the Covid pandemic. In the levetiracetam group 17 patients had a seizure and 32 did not (19 survived ≥ 12-months, 13 died within 12-months). In the no prophylaxis group 15 patients had a seizure and 30 did not (21 survived ≥12-months, 9 died within 12-months). Seventeen of the 36 evaluable levetiracetam patients (47%) had a seizure, compared with 15 of 36 evaluable no prophylaxis patients (41%) (OR 1.25, 95%CI 0.49-3.21, p=0.64). There were no levetiracetam related serious adverse events.

Conclusions The SPRING trial provides no evidence of a difference between levetiracetam and no prophylaxis in the 12-month seizure risk in patients undergoing glioma surgery, but the study was underpowered. The role of prophylactic anti-seizure medication remains undefined.

UCB-BioPharma supplied the Levetiracetam free of charge. They did not have any input or influence in the design and running of the trial. MDJ has received consultancy fees from Glaxo Smith Klein, Integra Health and Servier paid to University of Liverpool and from myTomorrows and Novocure paid personally. GT provides consultancy through University of Edinburgh to Scottish Brain Sciences for the development of clinical trials in dementia. LV has no current competing interests but was a member of the NIHR HTA Clinical Evaluation and Trials Committee 2014-2018. SCE has received consultancy fees from Servier. AGM has grant funding from Angelini Pharma and UCB Pharma paid to University of Liverpool, has received consultancy fees paid to University of Liverpool from GSK, Sanofi, Eisai and Jazz pharmaceuticals and is a NIHR Senior Invesitgator. RG was European Lead for the Vibes Study (Non intervention study of add on Lacosamide in resistant seizures in low grade glioma. All expert advice payments were donated to the brainstrust charity. CW, JC, JB, SL, RD, RW, CG, AGR, TR, HB have no competing interests.

ISCTRN: 70051203 EudraCT 2018-001312-30

https://fundingawards.nihr.ac.uk/award/16/31/136

This study was funded by the National Institute for Health Care Research Health Technology Assessment programme (NIHR-HTA) under grant agreement 16/31/136. Levetiracetam (Investigational Medical Product) was provided by UCB Pharma. The funders (NIHR and UCB Pharma) had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors had full access to all the data in the study and share the responsibility for the decision to submit for publication.

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