Intravenous Levetiracetam as First-line Anticonvulsive Treatment in Patients With Non-convulsive Status Epilepticus
Status:
Withdrawn
Trial end date:
2010-03-01
Target enrollment:
Participant gender:
Summary
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.
Phase:
Phase 2
Details
Lead Sponsor:
University Hospital, Basel, Switzerland
Collaborators:
Clinical Trial Unit, University Hospital Basel, Switzerland University Hospital, Basel, Switzerland, Dr. med. Stephan Rüegg, Neurology