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

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.

Inclusion Criteria:

1. 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.

2. Are undergoing cEEG monitoring in the neurologic intensive care unit (NICU) or other
closely monitored environment.

3. 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.

4. Are being considered for treatment with an IV AED.

5. Are at least 18 years old.

Exclusion Criteria:

1. Treatment with PHT, fPHT, or LCM in the last 7 days.

2. Contraindication for the use of fPHT or LCM.

3. 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).

4. Episodes of SE, defined as at least 30 minutes of ESz activity in 1 hour, in the last
6 hours.

5. Encephalopathic event secondary to acute anoxic/hypoxic event.

6. Undergoing therapeutic hypothermia protocol.

7. 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).

8. Electroencephalographic seizures consistent with typical absence seizures.

9. Evaluation for spell characterization or surgical treatment for epilepsy.

10. Pregnancy.