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

• ClinicalTrials.gov Identifier: NCT02726867
• Recruitment Status: Withdrawn
• First Posted: April 4, 2016
• Last Update Posted: August 29, 2017
• Sponsor: Mid-Atlantic Epilepsy and Sleep Center, LLC
• Information provided by (Responsible Party): Pavel Klein, Mid-Atlantic Epilepsy and Sleep Center, LLC

Tracking Information

• First Submitted Date: December 12, 2014
• First Posted Date: April 4, 2016
• Last Update Posted Date: August 29, 2017
• Study Start Date: February 2014
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 1, 2016)

Cessation of status epilepticus by EEG. [ Time Frame: 60 minutes ]

The cessation of ictal epileptic EEG activity measured by EEG.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 1, 2016)

Cessation of status epilepticus by clinical examination [ Time Frame: 60 minutes ]

Measurement of the time to status epilepticus cessation by clinical examination.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 1, 2016)

• Recurrence of status epilepticus. [ Time Frame: 72 hours ]
  The recurrence of status epilepticus in responders in during the 72 hours of monitoring.
• Rate of early treatment discontinuation [ Time Frame: 72 hours ]
  Rate of treatment discontinuation within 72 hours.
• Duration of hospitalization [ Time Frame: 3 months ]
  Investigators will count the number days of hospitalization.
• 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.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus
• Official Title: Evaluation of Efficacy and Safety of Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus
• 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)

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Epilepsy
• Status Epilepticus

Intervention

• Drug: levetiracetam
  Treatment will consist of LEV 4000 mg i.v. over 10 minutes.
  Other Name: Keppra
• Drug: lacosamide
  Treatment will consist of LCM 600 mg i.v. over 10 minutes
  Other Name: Vimpat
• Drug: Ketamine
  Treatment will consist of KET 2.5 mg/kg over 10 minutes
  Other Name: Ketalar
• Drug: Phenobarbital
  Treatment will consist of PHB 15 mg/kg mg i.v. at 100 mg/minute rate
  Other Name: Phenobarb

Study Arms

• 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.
  Intervention: Drug: levetiracetam
• 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.
  Intervention: Drug: lacosamide
• 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.
  Intervention: Drug: Ketamine
• 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.
  Intervention: Drug: Phenobarbital

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: August 28, 2017): 0
• Original Estimated Enrollment (submitted: April 1, 2016): 40
• Actual Study Completion Date: November 2016
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02726867
• Other Study ID Numbers: MAES-003
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pavel Klein, Mid-Atlantic Epilepsy and Sleep Center, LLC
• Study Sponsor: Mid-Atlantic Epilepsy and Sleep Center, LLC
• Collaborators: Not Provided

Investigators

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

• PRS Account: Mid-Atlantic Epilepsy and Sleep Center, LLC
• Verification Date: August 2017