Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures

Study Overview
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Brief Summary
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This a phase 2 study comparing the efficacy of intravenous (IV) lacosamide (LCM) with IV fosphenytoin (fPHT) in controlling frequent nonconvulsive seizures (NCSs), the Adverse Events profile of LCM compared with fPHT when used to treat frequent NCSs, and length of stay in an intensive care unit for subjects treated with LCM versus subjects treated with fPHT. The trial will include a preacute-treatment period, an acute-treatment period, a postacute-treatment period, and a long-term follow-up period.

Detailed Description
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Exploratory, prospective, multicenter, open-label, randomized study, in which the physicians who are interpreting cEEGs for treatment purposes and the central reviewers who are providing final cEEG interpretation for study purposes are all blinded to treatment. Initial LCM/maintenance doses: Subjects will receive a 400-mg IV initial bolus over 30 minutes, followed by a 2-hour post-dose observation-only period. If a breakthrough seizure occurs in the 6 hours following the 2-hour post-dose observation-only period, the subject will receive a 200-mg rebolus over 30 minutes. Regardless of whether a rebolus was administered, a maintenance dose of LCM will be started 12 hours after the initial bolus, and it will continue every 12 hours throughout the acute-treatment period. The daily maintenance dose will be equivalent to the total IV bolus per day (400 mg if no rebolus was administered or 600 mg if a rebolus was administered), divided into 2 doses. After completion of the acute-treatment period, daily maintenance with an AED will be at the discretion of the treating physician. Initial fPHT/maintenance doses: Subjects will receive a 20-mg PE/kg IV initial bolus at a rate no greater than 75 mg PE/minute, followed by a 2-hour post-dose observation-only period. If a breakthrough seizure occurs in the 6 hours following the 2-hour post-dose observation-only period, the subject will receive a 5-mg PE/kg IV rebolus at a rate no greater than 75 mg PE/minute. Regardless of whether a rebolus was administered, a maintenance dose of fPHT will be started 12 hours after the initial bolus, and it will continue every 12 hours throughout the acute-treatment period. The daily maintenance dose will be 5 mg PE/kg, divided into 2 doses. After completion of the acute-treatment period, daily maintenance with an AED will be at the discretion of the treating physician. Crossover/maintenance doses: If a subject does not receive a rebolus but has a seizure within 24 hours following the 2-hour post-initial-dose observation-only period, he or she will cross over and begin receiving the other drug, ie, the one not originally administered. If a subject does receive a rebolus and has another seizure within 24 hours following the 2-hour post-rebolus observation-only period, he or she will also cross over to the other drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period and rebolusing, if necessary. If a subject crosses over and starts receiving the second drug, in addition to receiving every-12-hours maintenance doses of the drug originally administered, the subject will also receive maintenance doses of the second drug every 12 hours, beginning 12 hours after the first dose of the second drug.

Official Title
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Utility of Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures

Conditions
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Nonconvulsive Seizures

Intervention / Treatment
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* Drug: fPHT
* Drug: LCM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have the capacity to understand and sign an institutional review board (IRB)-approved informed consent form (ICF) or have a legally authorized representative (LAR) available to sign on behalf of the subject. Are undergoing cEEG monitoring in the neurologic intensive care unit (NICU) or other closely monitored environment. Are experiencing NCSs according to the following criteria: At least 1 ESz lasting at least 10 seconds, with or without clinical correlates, occurring within the last 6 hours of cEEG monitoring. If a new AED has been started, ESzs must have occurred per the preceding bullet point at least 2 hours after starting that AED. If individual ESzs are not well defined, ESz time is at least 10 seconds and less than 30 minutes per hour of cEEG recording. Are being considered for treatment with an IV AED. Are at least 18 years old. Exclusion Criteria: Treatment with PHT, fPHT, or LCM in the last 7 days. Contraindication for the use of fPHT or LCM. Ongoing generalized convulsive status epilepticus (SE) (more than 2 generalized tonic-clonic seizures within 30 minutes without recovery to baseline or 1 seizure lasting longer than 10 minutes). Episodes of SE, defined as at least 30 minutes of ESz activity in 1 hour, in the last 6 hours. Encephalopathic event secondary to acute anoxic/hypoxic event. Undergoing therapeutic hypothermia protocol. Continuous EEG monitoring showing only periodic discharges or rhythmic delta activity without clear ESzs (for definitions of periodic discharges, rhythmic delta activity, and ESzs, see the Manual of Operations). Electroencephalographic seizures consistent with typical absence seizures. Evaluation for spell characterization or surgical treatment for epilepsy. Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: fPHT 20mg<br>fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. | Drug: fPHT<br>* If after initial treatment with fPHT any of the following occurs, the subject will have reached the end of the first treatment arm and will cross over and begin receiving the other drug, ie, the one not originally administered: the subject subsequently has another seizure within 24 hours following the 2-hour post-rebolus observation-only period; the subject does not receive a rebolus but has a seizure within 24 hours following the 2 hour post-bolus observation-only period; the subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period, rebolusing (if necessary), and study assessments with the second drug, beginning with the Baseline assessments.<br>* Other names: Cerebyx, Fosphenytoin;Drug: LCM<br>* If after initial treatment with LCM any of the following occurs, the subject will have reached the end of the first treatment arm and will cross over and begin receiving the other drug, ie, the one not originally administered: the subject subsequently has another seizure within 24 hours following the 2-hour post-rebolus observation-only period; the subject does not receive a rebolus but has a seizure within 24 hours following the 2 hour post-bolus observation-only period; the subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period, rebolusing (if necessary), and study assessments with the second drug, beginning with the Baseline assessments.<br>* Other names: Vimpat, Lacosamide;|
| Experimental: LCM 400mg<br>LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. | Drug: fPHT<br>* If after initial treatment with fPHT any of the following occurs, the subject will have reached the end of the first treatment arm and will cross over and begin receiving the other drug, ie, the one not originally administered: the subject subsequently has another seizure within 24 hours following the 2-hour post-rebolus observation-only period; the subject does not receive a rebolus but has a seizure within 24 hours following the 2 hour post-bolus observation-only period; the subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period, rebolusing (if necessary), and study assessments with the second drug, beginning with the Baseline assessments.<br>* Other names: Cerebyx, Fosphenytoin;Drug: LCM<br>* If after initial treatment with LCM any of the following occurs, the subject will have reached the end of the first treatment arm and will cross over and begin receiving the other drug, ie, the one not originally administered: the subject subsequently has another seizure within 24 hours following the 2-hour post-rebolus observation-only period; the subject does not receive a rebolus but has a seizure within 24 hours following the 2 hour post-bolus observation-only period; the subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period, rebolusing (if necessary), and study assessments with the second drug, beginning with the Baseline assessments.<br>* Other names: Vimpat, Lacosamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Experience no Nonconvulsive Seizures (NCS) for 24 Hours Following Treatment With LCM vs. fPHT, as Measured by Continuous Electroencephalography (cEEG) Monitoring. | Percentage of subjects who experience no nonconvulsive seizures (NCS) for 24 hours (after the 2-hour observation-only period) following treatment with LCM vs. fPHT, as measured by continuous electroencephalography (cEEG) monitoring with blinded review. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Functional Status as Measured by the Functional Disability Scale at Day 7 to 9 Postrandomization and Day 30 Post-randomization in the LCM vs fPHT Arms. | Change in functional status as measured by the Functional Disability Scale, using a 0-29 rating (0=w/o disability; 29=extreme vegetative state) at Day 7 to 9 postrandomization and Day 30 post-randomization in the LCM first, then fPHT versus fPHT first, then LCM arms. Data was analyzed in a manner consistent with determining if one treatment arm resulted in a greater change in functional status than the other. | Baseline to day 7-9, baseline to day 30 | 
| Percentage of All Subjects Who Have Had a Seizure, Are on Antiepileptic Drug (AED) Therapy, and Are Alive/Dead at Day 30 | Percentage of all subjects who have had a seizure, are on antiepileptic drug (AED) therapy, and are alive and dead at day 30. Data was acquired in a manner consistent with determining if one treatment arm (LCM first, then fPHT versus fPHT first, then LCM) resulted in a greater effect on seizures, antiepileptic drug (AED) use, and survival at day 30 after the acute treatment period. The acute treatment period could range from 6 to 30 hours. | both acute treatment periods to 30 days | 
| Percentage of Subjects Who Require a Rebolus of the Initial Antiepileptic Drugs (AED) to Control Nonconvulsive Seizures (NCS) in the LCM vs fPHT Arms. | The percentage of subjects who require a rebolus of the initial antiepileptic drug (AED) to control nonconvulsive seizures (NCS) in the LCM vs fPHT arms. | 24 hours | 
| Number of Subjects Who Required a Second Antiepileptic Drug (AED) to Control Nonconvulsive Seizures (NCS) | Number of subjects who required a second antiepileptic drug (AED) to control nonconvulsive seizures (NCS) | 24-26 hours | 
| Seizure Burden Change From Baseline to End of Initial Treatment | Absolute change in seizure time (defined as the number of minutes of electrographic seizure (ESz) activity per hour) before treatment and at the end of the first treatment arm. If less than 1 hour of recording time is available, seizure time will be extrapolated to 1 hour. The maximum amount of time that can be used to determine baseline seizure time is 6 hours. | Baseline, 24 hours | 
| Seizure Burden Change From Baseline to End of Crossover, Excluding Initial Treatment Arm | Absolute change defined as the number of minutes of ESz activity per hour before treatment and at the end of the second treatment arm. This measure does not evaluate seizure activity in the first treatment arm. If less than 1 hour of recording time is available, seizure time will be extrapolated to 1 hour. | baseline, 26-68 hours | 
| Time of First Bolus to End of Seizures After Initial Treatment Arm, Time From Crossover to End of Seizures in Crossover Treatment Arm | Time of first bolus to end of seizures after initial treatment arm, time from crossover to end of seizures in crossover treatment arm | time of first bolus to end of seizures after initial treatment arm, time from crossover to end of seizures in crossover treatment arm | 
| Number of Predefined Adverse Events (AE) After Treatment Arm 1 Administration | Number of predefined adverse events (AE) after treatment arm 1 administration. These predefined adverse events include Patients with at least one AE of interest, Cardiac disorders, investigations, suspected hypersensitivity reactions, vascular disorders, and hypotension. | 24 hours | 
| Percentage of Subjects in Whom Study Drug is Withdrawn Early After Treatment With Treatment Arm 1 | Percentage of subjects in whom study drug is withdrawn early after treatment with treatment arm 1 | baseline to end of treatment arm 1 | 
| Days in the Intensive Care Unit/Hospital | Data was acquired in a manner consistent with determining if one treatment arm (LCM first, then fPHT versus fPHT first, then LCM) resulted in more days of hospitalization than the other over the course of the study. | initial bolus to end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonconvulsive Seizures