Levetiracetam, Lacosamide and Ketamine as Adjunctive Treatment of Refractory Status Epilepticus
| Status: | Withdrawn |
|---|---|
| Conditions: | Neurology, Epilepsy |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 8/30/2017 |
| Start Date: | February 2014 |
| End Date: | November 2016 |
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)
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)
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
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
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
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