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Underpowered SPRING Trial Leaves Levetiracetam Prophylaxis in Glioma Surgery Unresolved
A phase III randomised controlled trial found no evidence of a difference in 12-month seizure risk between prophylactic levetiracetam and no prophylaxis in seizure-naive glioma patients, but the trial enrolled only 94 of its planned 804 participants, rendering any conclusion statistically unreliable. The result is formally neutral, though this reflects severe underpowering rather than a demonstrated equivalence between treatment arms.
What Was Studied
The SPRING trial investigated whether prophylactic levetiracetam, administered preoperatively and continued for at least one year postoperatively, could meaningfully reduce — by more than 50% — the risk of a first seizure within 12 months in seizure-naive patients with newly diagnosed cerebral glioma undergoing surgery. The question is clinically pressing because existing guidelines do not recommend routine antiseizure prophylaxis in this population, yet levetiracetam is widely prescribed perioperatively across neurosurgical centres, creating an evidence-practice gap with real consequences for patients.
How It Was Studied
SPRING was a two-arm, multicentre phase III randomised controlled trial conducted across 14 neurosurgery units in England and Scotland. Eligible participants were seizure-naive adults with suspected cerebral glioma who were scheduled for surgery; they were randomised to either prophylactic levetiracetam or no antiseizure medication (standard care). The trial incorporated an embedded health economic evaluation, with planned analyses of costs to the National Health Service and incremental cost per quality-adjusted life-year. Recruitment ran from October 2019 to August 2022, yielding 94 participants ranging in age from 24 to 79 years — just 12% of the target sample size of 804. Analyses followed the intention-to-treat principle, and secondary outcomes included time to first seizure, overall survival, progression-free survival, and patient-reported measures of mood, fatigue, memory, and quality of life.
What Was Observed
- No statistically meaningful difference in 12-month seizure occurrence was detected between the levetiracetam and control groups, though the trial was too small to draw any reliable conclusion from this finding. The absence of a detected effect cannot be interpreted as evidence that levetiracetam is ineffective.
- Approximately one quarter of enrolled patients died within the 12-month follow-up window and therefore never reached the primary endpoint, further reducing the effective sample available for the primary analysis. This is consistent with the aggressive natural history of high-grade glioma.
- The trial’s target sample size was 804 participants, designed to detect a greater than 50% reduction in seizure risk; only 94 were ultimately recruited, meaning the study was powered to detect no clinically meaningful difference and all results carry substantial imprecision.
- Evidence regarding cost-effectiveness was described as limited, and no robust conclusion about the incremental cost per quality-adjusted life-year could be drawn given the truncated sample.
Why This Matters
Seizures affect 50–80% of glioma patients over their lifetime, with roughly half proving drug-resistant — making primary prevention an appealing target. Despite guideline recommendations against routine prophylaxis, perioperative levetiracetam use remains common in neurosurgical practice, reflecting genuine clinical uncertainty. SPRING represents the most rigorously designed prospective trial yet attempted on this question, and its investigators note that its dataset — despite being small — constitutes the highest-quality evidence currently available and should contribute to a future individual patient data meta-analysis that may ultimately resolve the question.
How to Read This Result
This neutral result should be interpreted with considerable caution: the trial was severely underpowered, enrolling only about 12% of its intended participants primarily due to COVID-19-related recruitment delays, and it is therefore unable to confirm, refute, or quantify any treatment effect of prophylactic levetiracetam in this population.
Limitations
The most consequential limitation is early closure due to slow recruitment compounded by the COVID-19 pandemic, leaving the trial with far less than the statistical power required to test its primary hypothesis. Additionally, approximately one quarter of patients died within 12 months of randomisation without experiencing or being assessed for the primary seizure outcome, which further reduced the evaluable population and introduced informative censoring. Together, these factors mean that neither efficacy nor safety conclusions can be drawn with confidence, and the clinical question of whether levetiracetam prophylaxis benefits seizure-naive glioma patients undergoing surgery formally remains unanswered.