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

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ClinicalTrials.gov Identifier: NCT02726867
Recruitment Status : Withdrawn (No participants enrolled)
First Posted : April 4, 2016
Last Update Posted : August 29, 2017
Sponsor:
Information provided by (Responsible Party):
Pavel Klein, Mid-Atlantic Epilepsy and Sleep Center, LLC

Brief Summary:
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)

Condition or disease Intervention/treatment Phase
Epilepsy Status Epilepticus Drug: levetiracetam Drug: lacosamide Drug: Ketamine Drug: Phenobarbital Phase 3

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  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Efficacy and Safety of Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus
Study Start Date : February 2014
Actual Primary Completion Date : November 2016
Actual Study Completion Date : November 2016


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 Name: 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 Name: 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 Name: 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 Name: Phenobarb




Primary Outcome Measures :
  1. Cessation of status epilepticus by EEG. [ Time Frame: 60 minutes ]
    The cessation of ictal epileptic EEG activity measured by EEG.


Secondary Outcome Measures :
  1. Cessation of status epilepticus by clinical examination [ Time Frame: 60 minutes ]
    Measurement of the time to status epilepticus cessation by clinical examination.


Other Outcome Measures:
  1. Recurrence of status epilepticus. [ Time Frame: 72 hours ]
    The recurrence of status epilepticus in responders in during the 72 hours of monitoring.

  2. Rate of early treatment discontinuation [ Time Frame: 72 hours ]
    Rate of treatment discontinuation within 72 hours.

  3. Duration of hospitalization [ Time Frame: 3 months ]
    Investigators will count the number days of hospitalization.

  4. Number of participants with neurological deficit. [ Time Frame: 3 months ]
    Investigators will identify the number of patients with neurological deficit at 3 months are the other measure outcomes.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02726867


Locations
United States, Maryland
MidAtlantic Epilepsy and Sleep Center
Bethesda, Maryland, United States, 20817
Sponsors and Collaborators
Mid-Atlantic Epilepsy and Sleep Center, LLC
Investigators
Principal Investigator: Pavel Klein, M.D. Mid-Atlantic Epilepsy and Sleep Center

Responsible Party: Pavel Klein, M.D., Mid-Atlantic Epilepsy and Sleep Center, LLC
ClinicalTrials.gov Identifier: NCT02726867     History of Changes
Other Study ID Numbers: MAES-003
First Posted: April 4, 2016    Key Record Dates
Last Update Posted: August 29, 2017
Last Verified: August 2017

Keywords provided by Pavel Klein, Mid-Atlantic Epilepsy and Sleep Center, LLC:
refractory status epilepticus
levetiracetam
lacosamide
ketamine

Additional relevant MeSH terms:
Status Epilepticus
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Ketamine
Phenobarbital
Etiracetam
Lacosamide
Piracetam
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticonvulsants
Nootropic Agents
Neuroprotective Agents
Protective Agents
Hypnotics and Sedatives
GABA Modulators
GABA Agents