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.
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.
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.
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.
Huntington Memorial Hospital
Pasadena, California, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Emory University School of Medicine
Atlanta, Georgia, United States
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.
Time frame: 24 hours
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.
Time frame: 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)
Time frame: 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.
Time frame: 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.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
74
Massachusetts General Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Brigham and Woman's Hospital
Boston, Massachusetts, United States
Mission Hospital
Asheville, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
...and 1 more locations
Time frame: 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 frame: 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.
Time frame: 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
Time frame: 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.
Time frame: initial bolus to end of study
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.
Time frame: 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.
Time frame: both acute treatment periods to 30 days