Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus

Evaluation of Efficacy and Safety of Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus

The purpose of the study is to evaluate the efficacy and safety of levetiracetam , lacosamide and ketamine treatment of refractory status epilepticus. This will be a randomized, open-label, four-arm pilot study comparing time to cessation of refractory status epilepticus, determined by continuous EEG monitoring, in patients with refractory status epilepticus. Patients with status epilepticus who have been treated with standard dose lorazepam (or midazolam) and ≥ 1000 mg phenytoin with documented levels of ≥20 mg/ml and continue to have clinical status epilepticus for ≥1-24 hours after phenytoin loading will receive intravenously (i.v.) either 4000 mg levetiracetam, 600 mg lacosamide (Group B), 2.5 mg/kg ketamine or phenobarbital 15 mg/kg phenobarbital (Group D)

Study Overview

• Status: Withdrawn
• Conditions: Epilepsy; Status Epilepticus
• Intervention / Treatment: Drug: levetiracetam; Drug: lacosamide; Drug: Ketamine; Drug: Phenobarbital

Detailed Description

40 18-70 year old men and women with refractory status epilepticus, defined as status epilepticus continuing for >1 hour after completion of standard treatment with lorazepam (or midazolam) and i.v. phenytoin (or fos-phenytoin),will be enrolled. Participants will be randomized into four treatment arms, levetiracetam 4000 (Group A, n=10), lacosamide 600 mg (Group B, n=10), ketamine 2.5 mg/kg (group C,n=10),and phenobarbital 15 mg/kg (Group D, n=10) in a 1:1:1:1 ratio. Baseline evaluations will include continuous EEG, phenytoin levels prior to study intervention, CBC, CMP, serum Ca, Po4 and Mg.

Treatment will consist of levetiracetam 4000 mg i.v. over 10 minutes, lacosamide 600 mg i.v. over 10 minutes, ketamine 2.5 mg/kg over 10 minutes, or phenobarbital 15 mg/kg mg i.v. at 100 mg/minute rate.

Participants will be evaluated with ongoing physical examination and continuous EEG monitoring. Continuous EEG monitoring will be started before initiation of the study treatment, with documentation of electrographic status epilepticus. It will continue throughout the treatment period. Subjects will be observed for 1 hour clinically and with continuous EEG monitoring for cessation of SE. Participants in whom status epilepticus stops within 60 minutes of completion of study treatment will continue to receive phenytoin (150 mg i.v. q 12 hours, standard dose) and the study medication (levetiracetam 1500 mg i.v. q 12 hourly, lacosamide 300 mg q 12 hourly, ketamine 50 mg qid (vs. 40 mcg/kg/min i.v. infusion, as clinically applicable, or phenobarbital 90 mg i.v. q 12 hourly). Continuous EEG monitoring will continue for 72 hours to monitor for relapse of status epilepticus. Participants in whom status epilepticus fails to stop within 60 minutes after completion of study treatment ("non-responders") will undergo standard treatment with medically-induced coma, with intubation/ventilation and i.v. midazolam or propofol treatment at a dose to be titrated to EEG effect of "burst suppression" or suppression of all background activity. All patients, responders and non-responders alike, will continue treatment with phenytoin i.v., 150 mg q 12 hourly or, for conscious patients, 300 mg p.o. qhs for 72 hours after completion of study treatment. In patients requiring medical coma after study treatments (non-responders), medical coma will be discontinued after 48 hours. All participants will continue to be monitored with continuous EEG for 72 hours from completion of study treatment. If status epilepticus returns during this time, medical coma will be re-instituted and patients will be treated according to standard clinical care for prolonged SE

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Midatlantic Epilepsy and Sleep Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-70
2. Ability and willingness by surrogates to signed informed consent form.
3. Clinically and electrographically documented ongoing SE lasting ≥1 hour- ≤24 hours

Exclusion Criteria:

1. Creatinine > 2.5 mg/dl
2. Any systemic illness or unstable medical condition that might pose additional risk, including: cardiac, metabolic or endocrine disturbances, renal or liver disease
3. Active drug or alcohol dependence or any other factors that, in the opinion of the site investigators would interfere with adherence to study requirements
4. Pregnancy
5. Inability or unwillingness of subject or legal surrogate to give written informed consent
6. Known allergy to a study drug
7. Hypo- or hyperglycemia as cause of SE

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: levetiracetam; Patients with status epilepticus who have been treated with standard dose lorazepam (or midazolam) and ≥ 1000 mg phenytoin with documented levels of ≥20 mg/ml and continue to have clinical SE for ≥1-24 hours after phenytoin loading will receive intravenously (i.v.) 4000 mg levetiracetam.	Drug: levetiracetam; Treatment will consist of LEV 4000 mg i.v. over 10 minutes.; Other Names: Keppra
Active Comparator: lacosamide; Patients with status epilepticus who have been treated with standard dose lorazepam (or midazolam) and ≥ 1000 mg phenytoin with documented levels of ≥20 mg/ml and continue to have clinical SE for ≥1-24 hours after phenytoin loading will receive intravenously (i.v.) 600 mg lacosamide.	Drug: lacosamide; Treatment will consist of LCM 600 mg i.v. over 10 minutes; Other Names: Vimpat
Active Comparator: ketamine; Patients with status epilepticus who have been treated with standard dose lorazepam (or midazolam) and ≥ 1000 mg phenytoin with documented levels of ≥20 mg/ml and continue to have clinical SE for ≥1-24 hours after phenytoin loading will receive intravenously (i.v.) 2.5 mg/kg ketamine.	Drug: Ketamine; Treatment will consist of KET 2.5 mg/kg over 10 minutes; Other Names: Ketalar
Active Comparator: phenobarbital; Patients with status epilepticus who have been treated with standard dose lorazepam (or midazolam) and ≥ 1000 mg phenytoin (PHT) with documented levels of ≥20 mg/ml and continue to have clinical SE for ≥1-24 hours after PHT loading will receive intravenously (i.v.) phenobarbital 15 mg/kg.	Drug: Phenobarbital; Treatment will consist of PHB 15 mg/kg mg i.v. at 100 mg/minute rate; Other Names: Phenobarb

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cessation of status epilepticus by EEG.	The cessation of ictal epileptic EEG activity measured by EEG.	60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cessation of status epilepticus by clinical examination	Measurement of the time to status epilepticus cessation by clinical examination.	60 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of status epilepticus.	The recurrence of status epilepticus in responders in during the 72 hours of monitoring.	72 hours
Rate of early treatment discontinuation	Rate of treatment discontinuation within 72 hours.	72 hours
Duration of hospitalization	Investigators will count the number days of hospitalization.	3 months
Number of participants with neurological deficit.	Investigators will identify the number of patients with neurological deficit at 3 months are the other measure outcomes.	3 months

Collaborators and Investigators

• Sponsor: Mid-Atlantic Epilepsy and Sleep Center, LLC
• Investigators: Principal Investigator: Pavel Klein, M.D., Mid-Atlantic Epilepsy and Sleep Center

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: December 12, 2014
• First Submitted That Met QC Criteria: April 1, 2016
• First Posted (Estimate): April 4, 2016

Study Record Updates

• Last Update Posted (Actual): August 29, 2017
• Last Update Submitted That Met QC Criteria: August 28, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: ketamine; lacosamide; refractory status epilepticus; levetiracetam
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Status Epilepticus; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Membrane Transport Modulators; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nootropic Agents; Cytochrome P-450 CYP2B6 Inducers; Ketamine; Lacosamide; Levetiracetam; Phenobarbital
• Other Study ID Numbers: MAES-003