Levetiracetam Compared to Magnesium Sulfate for Prevention of Eclamptic Seizure

Levetiracetam Compared to Magnesium Sulfate for Prevention of Eclamptic Seizure: A Randomized Controlled Trial Study Protocol

1. Study Title: Levetiracetam Compared to Magnesium Sulfate for Prevention of Eclamptic Seizure: A Randomized Controlled Trial (LEVMag Trial) 2. Objectives

* Primary Objective: To assess whether Levetiracetam is non-inferior to Magnesium Sulfate in preventing eclamptic seizures in laboring and postpartum women with severe preeclampsia and HELLP syndrome. * Secondary Objectives: To compare the safety profiles, maternal and neonatal outcomes, and incidence of adverse events between the two study medications. 3. Study Design

* Design: Prospective, randomized, controlled, open-label, non-inferiority trial. * Setting: Single Urban Level III Obstetric Facility * Duration: 72-84 months (including recruitment, treatment, and follow-up). 4. Study Population

* Inclusion Criteria:

* Pregnant or postpartum women aged 19 years or older * Diagnosed with preeclampsia with severe features, superimposed preeclampsia or HELLP syndrome * At risk for eclampsia and eligible for seizure prophylaxis * Less than 2 hours exposure to magnesium sulfate or greater than 48 hours since last dose. * Exclusion Criteria:

* \<32 weeks estimated gestational age * History of epilepsy or seizure disorders unrelated to pregnancy * Allergy or contraindication to Levetiracetam or Magnesium Sulfate * Severe renal impairment (Oliguria \<120ml in 4 hours) * Plan for neonatal comfort care 5. Intervention/Comparator

* Intervention Arm: Levetiracetam 1g PO followed by Levetiracetam 1500 mg/day immediate release PO in 3 divided doses. Divided doses to begin 8 hours after initial 1g loading dose. * Control Arm: Magnesium Sulfate 4gm IV over 15-20min followed by 2gm/hr IV infusion (current hospital protocol). 6. Outcome Measures

* Primary Outcome:

o Incidence of eclamptic seizures from enrollment to discharge from delivery hospitalization. * Secondary Outcomes:

* Composite outcome of adverse events and severe adverse events * Neonatal 1 and 5 minute Apgar scores, NICU admission, length of respiratory support, neonatal death and stillbirth 7. Sample Size and Power Calculation

• Assumptions: * Expected seizure incidence with Magnesium Sulfate: 0.5% * Non-inferiority margin: 1% * Power: 80% * Alpha: 0.05 (one-sided) * Sample size per group: 620 * Total sample size: 1,240 8. Randomization Technique

• Permuted randomization scheme will be used. * Participants will be randomized 1:1 using a computer-generated randomization tool. * Block randomization with variable block sizes (4,6,8) will ensure balance between groups. * Allocation concealment will be maintained using sealed, opaque envelopes. 9. Enrollment

* We are collaborating with the Pharmacy Department to improve timing of patient enrollment. In addition to trained research nurses, participating Pharmacists will be CITI certified. * Patients will be identified when an order is entered for Magnesium Sulfate for seizure prophylaxis. A research pharmacist, research RN or principal investigator will then review the chart to ensure the patient meets study inclusion criteria. * For patients that meet inclusion criteria they will be approached in the location they are receiving care to review consent forms and be provided the patient bill of rights. * Those choosing to participate and completing the consent process will then be randomized. The next randomization envelope will be opened to determine their assigned treatment group and pharmacist will enter the appropriate orders. * Due to the urgent nature of this treatment, our goal is to complete enrollment and study assignment in sixty minutes or less after the initial order is received. 10. Adverse Event Reporting

* Adverse events (AEs) and serious adverse events (SAEs) will be recorded and reported in accordance with ICH-GCP guidelines (see below). * SAEs will be reported to the IRB and Data Safety Monitoring Board (DSMB) within 24 hours of when they are identified. * Interim safety analyses will be performed by the DSMB every 300 enrolled patients. * DSMB- 1 outside MFM provider, 1 non PI Methodist MFM, 1 Methodist OB provider. 11. Ethical Considerations and Informed Consent

* Approval will be obtained from the Institutional Review Board (IRB) and registered with clinicaltrials.gov once IRB approval is attained. * Participants will be provided with a detailed informed consent form outlining study procedures, risks, and rights.

Study Justification and Protocol Clarifications Modern anti-epileptic drugs have not been evaluated in their ability to prevent eclamptic seizures. The last studies comparing magnesium sulfate were performed against Nimodipine, a calcium channel blocker, over 20 years ago and phenytoin around 30 years ago. Magnesium sulfate is the current gold standard for seizure prophylaxis in women with hypertensive disease of pregnancy. It is a high risk medication that requires careful management and titration due to the risk for toxicity, respiratory depression, cardiac arrhythmia and death. Despite the high risk nature of a magnesium drip there has not been recent effort to identify safer medications for the prevention of eclamptic seizures. The study authors advocate for the study of Levetiracetam commercially known as Keppra®.

Levetiracetam is FDA approved for tonic-clonic seizures and is already used during pregnancy with an excellent safety profile in women with epilepsy (see appendix A). Use in this trial would be short term (likely 36-96 hours) and in late preterm or term pregnancies. This poses no risk for fetal malformation or birth defects as organogenesis is completed by 12 weeks and the study will enroll patients after 32 weeks gestation. As noted, levetiracetam has demonstrated safety in pregnancy in women with epilepsy and is safe in women who are breastfeeding. It has few significant complications specific to the medication itself and the short-term nature of the use in this study further mitigates those risks. Immediate release levetiracetam reaches maximum concentration in the blood in approximately 1 hour. Magnesium sulfate reaches a peak in 30 minutes when a bolus is given with levels falling by 60 minutes to roughly 2x physiologic levels, but typically below the 2mmol/L that is academically thought to be therapeutic. There is no currently established therapeutic dose based on scientific data. It is not recommended to routinely check magnesium levels during infusion unless there is concern for toxicity or renal impairment.

Inclusion/Exclusion - the reasoning behind our various criteria are related to state law, drug metabolism and to prevent confounders. Patients under 32 weeks gestation are excluded as they should receive magnesium sulfate for fetal neuroprotection and this exposure would confound the exposure groups, 19 y/o is the age of consent in Nebraska and renal impairment is important as both magnesium sulfate and levetiracetam are renally cleared. Since magnesium is rapidly cleared from the body we are choosing to include patients with less than 2 hours of exposure to magnesium or who have not received magnesium in the last 48 hours as we feel this does not clinically confound results due to short duration of exposure or complete clearance of the medication after prior exposure.

Dosing for magnesium is based on medically standardized protocol and Levetiracetam dosing is based on adult dosing in non-pregnant individuals with tonic-clonic seizures.