- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00603135
Intravenous Levetiracetam as First-line Anticonvulsive Treatment in Patients With Non-convulsive Status Epilepticus (Keppra)
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Basel, Switzerland, 4031
- University Hospital Basel
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: A
|
No effect after 30 min, standard therapy with f.e.
lorazepam for NCSE
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Efficacy/ Clinical and/or electroencephalographic cessation of SE
Time Frame: 30 min
|
30 min
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
safety
Time Frame: 48 hrs
|
48 hrs
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Stephan Rüegg, MD, Neurology
- Study Chair: Stephan Rüegg, MD, Neurology
Publications and helpful links
General Publications
- 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. doi: 10.1016/j.eplepsyres.2006.10.011. Epub 2006 Dec 8.
- Ruegg 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. doi: 10.1007/s11940-003-0001-4.
- 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. doi: 10.1111/j.1528-1167.2006.00586.x.
- 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 infusion compared with placebo in healthy subjects. Clin Ther. 2006 May;28(5):734-44. doi: 10.1016/j.clinthera.2006.05.004.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- MNeuro_Keppra_
- EKBB 272/27
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Status Epilepticus, Non-Convulsive
-
University of Southern DenmarkAarhus University Hospital; Copenhagen University Hospital, Denmark; University...RecruitingNon-Convulsive Status EpilepticusDenmark
-
Marinus PharmaceuticalsCompletedEpilepsy | Status Epilepticus | Convulsive Status EPILEPTICUS | Non Convulsive Status EpilepticusUnited States
-
Sohag UniversityCompletedStatus Epilepticus | Generalized Convulsive Status Epilepticus | Status Epilepticus, Generalized | Status Epilepticus, Generalized ConvulsiveEgypt
-
Hospital Universitari de BellvitgeHospital Clinic of Barcelona; Institut d'Investigació Biomèdica de Girona Dr... and other collaboratorsCompletedGrand Mal Status Epilepticus | Non-convulsive Status EpilepticusSpain
-
University Children's Hospital, ZurichPediatric Emergency Department, Inselspital Bern, Switzerland; Pediatric Neurology...RecruitingStatus Epilepticus | Altered Mental Status | Non-Convulsive Status EpilepticusSwitzerland
-
Xuanwu Hospital, BeijingUnknownGeneralized Convulsive Status EpilepticusChina
-
Assiut UniversityNot yet recruitingConvulsive Status EPILEPTICUS
-
Sohag UniversityRecruitingGeneralized Convulsive Status EpilepticusEgypt
-
Assistance Publique - Hôpitaux de ParisCompletedIntensive Care Unit | Generalized Convulsive Status EpilepticusFrance
-
Assistance Publique - Hôpitaux de ParisCompletedConvulsive Status EPILEPTICUSFrance
Clinical Trials on first-line i/v-levetiracetam
-
Novartis PharmaceuticalsActive, not recruiting
-
Grupo Argentino de Tratamiento de la Leucemia AgudaRecruitingLymphoma, Non-Hodgkin's, AdultArgentina
-
Kessler FoundationUCB PharmaActive, not recruitingStroke | AphasiaUnited States
-
French Innovative Leukemia OrganisationAbbVie; AstraZeneca; BeiGene; Janssen-Cilag Ltd.Recruiting
-
Peking University People's HospitalPeking University Shougang HospitalCompletedPrognosis | Clinical Response | Histopathological ResponseChina
-
Joint AcademyLund University; The Swedish Osteoarthritis RegistryRecruitingOsteoarthritis | First-line Treatment | Health Services AccessibilitySweden
-
National Cancer Institute, NaplesActive, not recruiting
-
CHU de ReimsUnknown
-
Rennes University HospitalInstitut National de Recherche pour l'Agriculture, l'Alimentation et l'EnvironnementCompletedNeurocognitive Correlates of Eating HabitsFrance
-
Guang'anmen Hospital of China Academy of Chinese...RecruitingAdvanced Colorectal CarcinomaChina