Clinical trial NCT01458522: Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures
Official title: Utility of Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonconvulsive Seizures
Keywords: Nonconvulsive Seizures
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: UCB Pharma
First posted: 2011-10-25
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 24 hours
Secondary outcomes:
measure: Percentage of Subjects Who Require a Rebolus of the Initial Antiepileptic Drugs (AED) to Control Nonconvulsive Seizures (NCS) in the LCM vs fPHT Arms.
timeFrame: 24 hours
measure: Number of Subjects Who Required a Second Antiepileptic Drug (AED) to Control Nonconvulsive Seizures (NCS)
timeFrame: 24-26 hours
measure: Seizure Burden Change From Baseline to End of Initial Treatment
timeFrame: Baseline, 24 hours
measure: Seizure Burden Change From Baseline to End of Crossover, Excluding Initial Treatment Arm
timeFrame: baseline, 26-68 hours
measure: Time of First Bolus to End of Seizures After Initial Treatment Arm, Time From Crossover to End of Seizures in Crossover Treatment Arm
timeFrame: time of first bolus to end of seizures after initial treatment arm, time from crossover to end of seizures in crossover treatment arm
measure: Number of Predefined Adverse Events (AE) After Treatment Arm 1 Administration
timeFrame: 24 hours
measure: Percentage of Subjects in Whom Study Drug is Withdrawn Early After Treatment With Treatment Arm 1
timeFrame: baseline to end of treatment arm 1
measure: Days in the Intensive Care Unit/Hospital
timeFrame: initial bolus to end of study
measure: 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.
timeFrame: Baseline to day 7-9, baseline to day 30
measure: Percentage of All Subjects Who Have Had a Seizure, Are on Antiepileptic Drug (AED) Therapy, and Are Alive/Dead at Day 30
timeFrame: both acute treatment periods to 30 days
Other outcomes:
Locations:
city: Pasadena
country: United States
facility: Huntington Memorial Hospital
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Woman's Hospital
state: Massachusetts
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center Dallas
state: Texas
Study officials:
affiliation: Duke Clinical Research Institute
name: Aatif Husain, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Belcastro V, Vidale S, Pierguidi L, Sironi L, Tancredi L, Striano P, Taborelli A, Arnaboldi M. Intravenous lacosamide as treatment option in post-stroke non convulsive status epilepticus in the elderly: a proof-of-concept, observational study. Seizure. 2013 Dec;22(10):905-7. doi: 10.1016/j.seizure.2013.07.011. Epub 2013 Aug 13.