Levetiracetam for Seizure Prevention After Brain Tumor Surgery

Phase 3Not Yet RecruitingNCT07239115

Beijing Tiantan Hospital558 enrolled

Overview

This study aims to evaluate the efficacy and safety of levetiracetam for the prevention of postoperative seizures in adult patients undergoing supratentorial brain tumor surgery. It is a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. Eligible participants will be randomly assigned in a 1:1 ratio to receive levetiracetam or placebo, starting 1 hour before surgery and continuing for 3 months postoperatively. The primary outcome is the incidence of clinical seizures within 3 months after surgery. Secondary outcomes include subclinical seizures within 7 days and 3 months postoperatively, adverse events within 3 months, and health economic outcomes. The study aims to clarify the role of levetiracetam in the primary prevention of perioperative seizures in brain tumor patients and to provide evidence for rational use of antiseizure medications in neurosurgical practice.

Seizures are a common complication in brain tumor patients, particularly after supratentorial craniotomy, with approximately two-thirds occurring within the first postoperative month and affecting both early recovery and long-term outcomes. Although prophylactic ASMs are widely used in practice, there is no consensus on whether routine prophylaxis is necessary or on the optimal regimen. Major societies generally conclude that evidence is insufficient to recommend for or against routine use, while some national guidance provides conditional suggestions only for "high-risk" patients-highlighting the lack of robust data. Real-world studies also show high but heterogeneous use and no unified standard. A high-quality randomized trial is therefore required to determine the necessity, efficacy, and safety of routine prophylaxis. The PREVENT trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of levetiracetam in adults undergoing supratentorial tumor resection without a prior seizure history, and thereby to assess the need for routine perioperative prophylaxis. Participants are randomized 1:1 with center-stratified block allocation. The dosing regimen is: one intravenous dose 1 hour preoperatively and another on the evening after surgery, followed by oral/NG maintenance (0.5 g twice daily) through postoperative month 3; the control arm receives matching placebo. Standard antiseizure treatment is provided if seizures occur and these events are recorded as endpoints. Scheduled assessments occur at screening, day of surgery, postoperative day 7, month 3 (±7 days), and month 6 (±10 days). The primary endpoint is clinical seizures within 3 months after surgery, adjudicated by predefined criteria. Secondary endpoints are subclinical seizures within 7 days and 3 months (based on standardized EEG review). Exploratory endpoints include direct medical costs and direct non-medical/indirect costs at 3 months, and clinical seizures within 6 months. Safety endpoints include adverse events, serious adverse events, and death through 3 months. The principal null hypothesis is no difference between groups. Efficacy is analyzed primarily in the full analysis set (FAS) with per-protocol (PPS) as supportive; center effects are modeled, two-sided α=0.05, and results reported as risk differences with 95% CIs and relative risks. The planned sample size is 558 participants across \~10 centers, with independent safety oversight. This trial will provide robust randomized evidence on the necessity, benefits, risks, and economic impact of routine perioperative prophylaxis to guide standardized clinical practice.

Interventions

LevetiracetamDRUG

Levetiracetam 500 mg (5 mL) for intravenous infusion administered 1 hour before surgery and again on the evening after surgery (approximately 20:00-22:00), diluted in 100 mL 0.9% sodium chloride or 5% glucose and infused over about 15 minutes. From postoperative day 2 through 3 months, oral levetiracetam tablets 0.5 g twice daily (or via nasogastric route if oral intake not feasible) are administered.

PlaceboDRUG

Matching placebo solution (5 mL) for intravenous infusion 1 hour before surgery and again on the evening after surgery (approximately 20:00-22:00), diluted in 100 mL 0.9% sodium chloride or 5% glucose and infused over about 15 minutes. From postoperative day 2 through 3 months, matching placebo tablets are given twice daily (oral or via nasogastric route). Placebo formulation, packaging, and administration schedule are identical to those of levetiracetam.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Undergoing craniotomy for supratentorial brain tumor resection. 2. Radiologically confirmed supratentorial brain tumor (excluding posterior fossa tumor, brainstem tumor, or gliomatosis cerebri). 3. Age between 18 and 75 years. 4. No history of seizures or epilepsy. 5. No prior use of antiepileptic drugs. 6. Karnofsky Performance Status (KPS) score ≥ 70. 7. Signed written informed consent Exclusion Criteria: 1. Concomitant brain injury (such as cerebrovascular accident, severe head trauma) or any intracranial disease other than tumor. 2. Pregnant or lactating women. 3. Intestinal stoma, cardiac disease, previous craniotomy for brain tumor resection, or intracranial infection. 4. Severe hepatic or renal dysfunction (defined as ALT or AST \>3× upper limit of normal; serum creatinine \>3.0 mg/dL \[265.2 μmol/L\] or eGFR \<30 mL/min/1.73m²). 5. Significant electrolyte imbalance (severe hyponatremia: serum sodium \<125 mmol/L; severe hypernatremia: serum sodium \>160 mmol/L; severe hypocalcemia: serum calcium \<2.5 mmol/L; or severe hypercalcemia: serum calcium \>6.5 mmol/L). 6. Long-term history of psychiatric disorders, alcoholism, or drug abuse. 7. Severe mental illness. 8. Allergy to or contraindication for antiepileptic drugs. 9. Unable to undergo MRI or EEG examination. 10. Deemed unsuitable for participation by the investigator. 11. Participation in another drug or device clinical trial within the past 3 months.

Outcomes

Primary Outcomes

Incidence of postoperative clinical seizures within 90 days after surgery

The occurrence of one or more postoperative clinical seizures within 90 days after supratentorial brain tumor resection, confirmed by treating physicians and reviewed by independent neurologists. A clinical seizure is defined as a transient occurrence of signs or symptoms resulting from abnormal excessive or synchronous neuronal activity in the brain, with or without electrographic correlation. Seizure episodes will be classified according to the International League Against Epilepsy (ILAE) 2017 operational classification

Time frame: Within 90 days after surgery

Secondary Outcomes

Incidence of postoperative subclinical seizures detected by EEG

Occurrence of subclinical epileptiform discharges or electrographic seizures detected by scalp EEG within 7 days and 3 months postoperatively, without clinical seizure manifestations. Recordings will be reviewed and confirmed by independent neurophysiologists.

Time frame: Within 7 days and 3 months after surgery

Safety outcomes: incidence of adverse events, serious adverse events, and all-cause mortality within 3 months after surgery

Composite safety outcomes include the proportion of participants experiencing any adverse events (AEs), serious adverse events (SAEs), or all-cause mortality within 3 months postoperatively. AEs and SAEs will be coded using MedDRA and evaluated for severity and relationship to study drug according to ICH-GCP definitions.

Time frame: Within 3 months after surgery