Status Epilepticus, Non-Convulsive Clinical Trial
— KeppraOfficial title:
Intravenous Levetiracetam as First-line Anticonvulsive Treatment in Patients With Non-convulsive Status Epilepticus
Status epilepticus (SE) represents the most common life-threatening neurological emergency
requiring treatment on an intensive care unit. The incidence in Western European countries
is about 12-18/100'000. Immediate and effective treatment of SE is obviously essential
because of the deleterious effects of continuous seizures on the brain and the whole
organism. Guidelines emphasize the use of benzodiazepines (BZD) as first-line anticonvulsive
drugs. Alternatively, i/v Phenytoin (PHE), fosphenytoin (FOS), and valproate (VPA) were also
tested as first-line anticonvulsants in SE. Direct comparison of PHE with lorazepam (LZP)
showed significant superiority of LZP (evidence class I). Other trials i/v PHE or -VPA are
of evidence class III or IV. BZD, VPA, and PHE have clinical and pharmacological
disadvantages. BZD may cause respiratory depression or sedation and may be not suitable for
patients with COPD or ambiguous in patients with BZD addiction. Some compounds also may
induce tachyphylaxis or accumulate under concomitant renal failure. PHE has saturable
metabolism subject to Michaelis-Menten kinetics increasing the risk of overdosing in an
acute setting causing liver damage, serious cardiac arrhythmias, hypotension, cerebellar
degeneration, peripheral neuropathy and local/systemic skin reactions. Although of
unequivocal efficacy, PHE should no longer be used for long-term because of its adverse
effects after chronic administration (irreversible cerebellar degeneration causing
debilitating ataxia, painful polyneuropathy, and osteopenia increasing the risk of
fractures). Metabolism by and self-induction of the hepatic CYP450 system make PHE prone to
interactions with several other drugs, notably other antiepileptics. VPA may cause liver
failure, hemorrhagic complications, pancreatitis, and hyperammonemic encephalopathy. To
summarize, these three first-line agents for the treatment of SE may cause serious side
effects in several patients with SE.
Levetiracetam (LEV) is broad-spectrum antiepileptic drug. It binds to the presynaptic
vesicular protein 2A abundantly present in different regions of the brain; LEV
presynaptically modulates transmitter release, but the exact mechanism(s) remain unclear.
Data also revealed that LEV stabilizes GABAA receptors upon repetitive activation what is
important in treatment of SE because GABAA receptors undergo significant changes of subunit
conformation within minutes after sustained activation like during SE. These changes render
GABAA receptors the less anticonvulsive, the longer SE lasts. Levetiracetam has a favorable
pharmacological profile with large safety margins. Its partly extrahepatic hydrolyzation
bypasses the CYP450 system; renal excretion is 60-70% unchanged, and 23-27% metabolized.
Dosage needs adjustment when renal function is impaired. LEV lacks interactions with any
drugs yet. Drowsiness is the most common side-effect while respiration, liver and kidney
function, and the blood system are not affected. LEV shows an important clinical effect even
after the first dose and maximal efficacy within the first week of drug-intake. The
favorable clinico-pharmacological profile predilects LEV for the first-line treatment of SE,
especially in patients with multi-organ failure, sepsis, coma etc.. About 10 % of comatous
patients may be in non-convulsive SE (NCSE) on ICU's. These patients are under
polymedication whereby interactions of the anticonvulsants approved yet for the treatment of
NCSE with their other drugs may have fatal effects. Conversely, non-interacting
anticonvulsants would represent an advantage for the treatment of NCSE for these patients.
Recently, the i/v formulation of LEV was approved by the FDA for the use in patients, but
not specifically for the treatment of SE. Data about the single-dose bioavailability of
i/v-LEV in comparison to oral tablets as well as multiple-dose pharmacokinetics and
tolerability in healthy subjects were recently published. In addition, the administration of
i/v-LEV dosages ranging from 2000-4000 mg within 15 minutes and of dosages ranging from
1500-2500 mg within 5 minutes was safe and well tolerated, and led to efficacious drug
levels in a randomized, single-blind, placebo-controlled safety and pharmacokinetic study in
healthy volunteers.
Slight somnolence is expected to be the only adverse effect of i/v LEV, sharply contrasting
with the sedation up to coma after i/v benzodiazepines. Thus, even severely ill patients
will be accessible to neurological tests under LEV which is a big advantage in this clinical
difficult setting of NCSE.
I-v LEV is considered an ideal candidate for the first-line use (before benzodiazepines) in
patients with NCSE, especially in those with important comorbidity and concomitant
polymedication. Thus, we would like to test the feasibility, safety, and efficacy of i/v-LEV
as first-line medication in a open-label, single-center, prospective pilot study as outlined
below.
| Status | Withdrawn |
| Enrollment | 0 |
| Est. completion date | March 2010 |
| Est. primary completion date | July 2009 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 20 Years and older |
| Eligibility |
Inclusion Criteria: - Patients 18 years old or older with NCSE. NCSE includes the following subtypes: - simple partial NCSE - complex partial status epilpeticus - Absence status - NCSE in critical illness - Written informed consent should be signed. Exclusion Criteria: - Age below 20 - Known intolerance to the study drug levetiracetam - Known pregnancy - Postanoxic SE - Subtle SE |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| Switzerland | University Hospital Basel | Basel |
| Lead Sponsor | Collaborator |
|---|---|
| University Hospital, Basel, Switzerland | Clinical Trial Unit, University Hospital Basel, Switzerland, University Hospital, Basel, Switzerland, Dr. med. Stephan Rüegg, Neurology |
Switzerland,
Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu ZS, Stockis A. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006 Jul;47(7):1128-35. — View Citation
Ramael S, De Smedt F, Toublanc N, Otoul C, Boulanger P, Riethuisen JM, Stockis A. Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous i — View Citation
Rüegg SJ, Dichter MA. Diagnosis and Treatment of Nonconvulsive Status Epilepticus in an Intensive Care Unit Setting. Curr Treat Options Neurol. 2003 Mar;5(2):93-110. — View Citation
Rupprecht S, Franke K, Fitzek S, Witte OW, Hagemann G. Levetiracetam as a treatment option in non-convulsive status epilepticus. Epilepsy Res. 2007 Mar;73(3):238-44. Epub 2006 Dec 8. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Efficacy/ Clinical and/or electroencephalographic cessation of SE | 30 min | Yes | |
| Secondary | safety | 48 hrs | Yes |