Levetiracetam Versus Carbamazepine in Post-Stroke Late Onset Crisis (EpIc)

Multicenter, Comparative, Randomized, Open Trial to Evaluate Efficacy and Safety of Levetiracetam Versus Carbamazepine in Post Stroke Late Onset Crisis

The principal purpose of the study is to determine the efficacy and safety of Levetiracetam versus Carbamazepine, intended as the number of patients free from crisis during the whole period of treatment, in patients affected by post stroke late onset crisis.

Study Overview

• Status: Unknown
• Conditions: Stroke; Epileptic Seizures
• Intervention / Treatment: Drug: Levetiracetam; Drug: Carbamazepine

Detailed Description

Stroke is the most common cause of seizures in the elderly and seizures are among the most common sequelae of stroke.

About 10% of patients experience seizures since stroke onset up to several years (Silverman 2002). Arbitrarly a cut point of 2 weeks divide early seizures from late seizures (Honey 2000, Olofson 2000, Berger 1989).Late occurrence of late seizure appears to carry a high risk for epilepsy (Wilmore 1990).

The risk of epilepsy in some patients with a single stroke-related seizure is high enough to justify starting an anticonvulsant therapy before a second seizure occurs(Labovitz 2003).

Levetiracetam (S-α-ethil-2-oxo-pyrrolidine acetamide) is S-enantiomer of a pyrrolidine derivative and is unrelated to any other AED and has a unique preclinical and clinical profile (Gower et al 1992).

Levetiracetam (LEV) binds with a stereospecific binding site in the CNS that is saturable and reversible (Noyer 1995). This site actually known as LBS Levetiracetam Binding Site) is unique and do not correspond to any known receptor or channel that might be involved in neuroexcitability (Gillard 2003).

LEV selectively inhibits N-type Ca2 channels of CA1 pyramidal hyppocampal neurons (Lukyanetz et a 2002) and, despite of not having any activity on GABA-gated currents, it shows a potent ability to reverse the inhibitory effects of the negative allosteric modulators zinc and β-carbolines on both GABAA and glycine receptor mediated responses(Rigo et al. 2002).

LEV has no effects on normal neurons (Birnstiel et al.1997) LEV as other AEDs has effect in decreasing repetitive neuronal firing, but only LEV reduces the number of cells firing synchronously (amplitude) of the evoked PS(Margineau and Klitgaard 2000).

The efficacy profile of the drug has been established through three pivotal randomized double blind, placebo controlled, parallel studies on 904 patients suffering from partial seizures secondarily or not generalised that were not well controlled by previous treatment (Shorvon et al. 2000; Ben-Menachem et al. 2000; Cereghino et al. 2000).In these three studies LEV showed a significant reduction of seizure frequency. A pooled analysis of the results from these three studies supports a dose-response effect for levetiracetam: responder rates were 28.5, 34.3 and 41.3 % for patients treated with levetiracetam 1000, 2000, 3000 mg/day respectively, as compared with 13.1% for placebo group. The respective values for complete seizure freedom were 4.7, 6.3, 8.6 and 0.8%(Privitera 2002, Boon et al, 2002).

In a review of data for 1422 patients treated with levetiracetam, 38.6% of patients experienced a ≥ 50% reduction in seizure frequency and 20% experienced a reduction of ≥ 75%. The present study is not blinded because one of the purposes with the study has been to mimic daily clinical practice as close as possible.

• Study Type: Interventional
• Enrollment (Anticipated): 630
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy, 60020
    • Not yet recruiting
    • Policlinico Umberto I
    • Principal Investigator: LEANDRO PROVINCIALI
  • Brindisi, Italy, 72100
    • Recruiting
    • Ospedale A. Perrino
    • Principal Investigator: BRUNO PASSARELLA
  • Catania, Italy, 95126
    • Not yet recruiting
    • Ospedale Cannizzaro
    • Principal Investigator: ERMINIO COSTANZO
  • Genova, Italy
    • Recruiting
    • Ospedale San Martino
    • Principal Investigator: carlo GANDOLFO
  • Imperia, Italy, 18100
    • Recruiting
    • Ospedale Civile Imperia ASL 1
    • Principal Investigator: Carlo SERRATI
  • Napoli, Italy, 80131
    • Recruiting
    • Ospedale A. Cardarelli-
    • Principal Investigator: MAURO PAGLIUCA, Dr.
  • Napoli, Italy, 80131
    • Not yet recruiting
    • Ospedale Cardarelli
    • Principal Investigator: VINCENZO ROSSI
  • Palermo, Italy, 90100
    • Not yet recruiting
    • Ospedale Civico
    • Principal Investigator: ERALDO NATALE'
  • Piacenza, Italy, 29100
    • Recruiting
    • Osp. Guglielmo da Saliceto
    • Principal Investigator: DONATA GUIDETTI
  • Reggio Emilia, Italy, 42100
    • Recruiting
    • Arcispedale S. Maria nuova
    • Principal Investigator: Romana RIZZI
  • Taranto, Italy
    • Recruiting
    • Ospedale SS. Annunziata - Ospedale Civile
    • Principal Investigator: saverio INTERNO'
  • Torino, Italy
    • Recruiting
    • Ospedale Molinette-Università di Torino
    • Principal Investigator: Dario GIOBBE
  • Trieste, Italy, 34149
    • Recruiting
    • Azienda Ospedaliera Universitaria Trieste
    • Principal Investigator: FABIO CHIODO GRANDI
  • AL
    • Novi Ligure, AL, Italy, 15057
      • Not yet recruiting
      • Ospedale S. Giacomo
      • Principal Investigator: MARCO AGUGGIA
  • CN
    • Cuneo, CN, Italy, 12100
      • Not yet recruiting
      • Ospedale S. Croce e Carle
      • Principal Investigator: ENZO GRASSO
  • GE
    • Genova, GE, Italy, 16132
      • Recruiting
      • Ospedale S. Martino
      • Principal Investigator: GIOVANNI REGESTA
  • MI
    • Rozzano, MI, Italy, 20089
      • Recruiting
      • Istituto Clinico Humanitas
      • Principal Investigator: GIUSEPPE MICIELI
  • PG
    • Città della Pieve, PG, Italy, 06062
      • Not yet recruiting
      • USL 2 Ospedale B.G. Villa
      • Principal Investigator: STEFANO RICCI
    • Foligno, PG, Italy
      • Recruiting
      • Ospedale Civile San Giovanni Battista di Foligno
      • Principal Investigator: Pierluigi BRUSTENGHI
    • Sant'Andrea delle Fratte, PG, Italy, 06131
      • Not yet recruiting
      • Ospedale Santa Maria della Misericordia
      • Principal Investigator: ANNA CANTISANI
  • PV
    • Pavia, PV, Italy, 27100
      • Not yet recruiting
      • Istituto Neurologico C. Mondino
      • Contact: Anna Cavallini, doctor
      • Principal Investigator: Anna Cavallini, doctor
  • RG
    • Vittoria, RG, Italy, 97019
      • Recruiting
      • Ospedale Guzzardi
      • Principal Investigator: FRANCESCO IEMOLO
  • VE
    • Portogruaro, VE, Italy, 30026
      • Recruiting
      • Ospedale di Portogruaro
      • Principal Investigator: SEBASTIANO D'ANNA
  • VV
    • Vibo Valentia, VV, Italy, 89900
      • Recruiting
      • Ospedale Civile
      • Principal Investigator: domenico consoli, doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients having a stroke (ischemic and haemorrhagic) showing (one) subsequent seizure 14 days up to 3 years after stroke
• Patients has signed the informed consent form
• Aged ≥ 18 years

Exclusion Criteria:

• Severe stroke patients with Rankin scale > 3
• Patients with a life expectancy of < 12 months
• Patients screened more than 15 days after first seizure
• Patients with a diagnosed epilepsy
• Patients with clear evidence of myoclonic seizures
• Patients with contraindication to levetiracetam and carbamazepine use
• Patients presenting epileptic status at onset
• Patients having a MMSE <24
• Patients having a seizure before stroke
• Patients taking any AED 4 weeks prior to randomisation in the study
• Patients showing dysphagia after stroke not able to swallow tablets.
• Patients with a low compliance for the study
• Pregnant women, lactating or sexually active women with childbearing potential who are not using a medically accepted birth control method.
• Allergy or intolerance to pyrrolidine derivatives and/or tablet excipients or to carbamazepine derivates and /or tablet excipients
• Patients involved in another clinical trial 30 days prior randomization
• Patients with any tumour
• Patients with previous traumatic brain accident resulting in impairment of consciousness.
• Patients for whom it is not possible to assess seizure onset

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LEV; Levetiracetam	Drug: Levetiracetam; Levetiracetam tablets 250-500 mg. The drug dosage will be up-titrated from 250 mg bid in the first 2 weeks to 500 mg bid during the rest of the treatment period. The dosage can be incremented until 1500 mg bid, at Investigator judgement if crisis continue, or it can be reduced in case of adverse events
Active Comparator: CAR; Carbamazepina	Drug: Carbamazepine; Carbamazepina tablets 200 mg. The drug dosage will be up-titrated from 100 mg die in the first 3 days to 100 mg bid during days 4 to 7, to 200 mg bid in the 2nd week, to 300 mg bid during the rest of the treatment period. The dosage can be incremented until 800 mg bid, at Investigator judgement if crisis continue, or it can be reduced in case of adverse events

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
number of patients free from post stroke recurrent crisis	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
To compare retention time of LEV vs CBZ since first intake throughout treatment period	one year
To compare time to second seizure in both treatments.	one year
To evaluate differences in cognitive function and in quality of life in levetiracetam and carbamazepine patients having post-stroke seizures at the end of treatment period	one year
evaluate EEG changes as compared with baseline with that obtained at the end of treatment period	one year
To compare seizure frequency in levetiracetam and carbamazepine groups throughout treatment period	one year
To evaluate the safety of levetiracetam versus carbamazepine throughout the treatment period	one year

Collaborators and Investigators

• Sponsor: Scienze Neurologiche Ospedaliere
• Investigators: Principal Investigator: domenico consoli, doctor, Ospedale Civile Vibo Valentia

Publications and helpful links

General Publications

• Rhoney DH, Tipps LB, Murry KR, Basham MC, Michael DB, Coplin WM. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology. 2000 Jul 25;55(2):258-65. doi: 10.1212/wnl.55.2.258.
• Angehagen M, Margineanu DG, Ben-Menachem E, Ronnback L, Hansson E, Klitgaard H. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. Neuroreport. 2003 Mar 3;14(3):471-5. doi: 10.1097/00001756-200303030-00035.
• Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol. 2002 Feb;59(2):195-201. doi: 10.1001/archneur.59.2.195.
• Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet. 2000 Apr 22;355(9213):1441-6. doi: 10.1016/S0140-6736(00)02149-8.
• Inzitari D. The Italian Guidelines for stroke prevention. The Stroke Prevention and Educational Awareness Diffusion (SPREAD) Collaboration. Neurol Sci. 2000 Feb;21(1):5-12. doi: 10.1007/s100720070112. No abstract available.
• Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993 May-Jun;34(3):453-68. doi: 10.1111/j.1528-1157.1993.tb02586.x.
• Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Cote R, Lebrun L, Pirisi A, Norris JW. Seizures after stroke: a prospective multicenter study. Arch Neurol. 2000 Nov;57(11):1617-22. doi: 10.1001/archneur.57.11.1617.
• Olafsson E, Gudmundsson G, Hauser WA. Risk of epilepsy in long-term survivors of surgery for aneurysmal subarachnoid hemorrhage: a population-based study in Iceland. Epilepsia. 2000 Sep;41(9):1201-5. doi: 10.1111/j.1528-1157.2000.tb00326.x.
• Berger AR, Lipton RB, Lesser ML, Lantos G, Portenoy RK. Early seizures following intracerebral hemorrhage: implications for therapy. Neurology. 1988 Sep;38(9):1363-5. doi: 10.1212/wnl.38.9.1363.
• Sung CY, Chu NS. Epileptic seizures in thrombotic stroke. J Neurol. 1990 Jun;237(3):166-70. doi: 10.1007/BF00314589.
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• - Klitgaard H, Pitkanen A, Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam. Epileptic disorder 2003; 5:S9-S16 - Kraemer G, Eldrich P. Levetiracetam in Elderly patients with epilepsy - The American Eplepsy Society and The American Clinical Neurophysiology Society - Joint Meeting November 30-December 5, 2001 - Krakow K, Walker M, Otoul C, Sander JWAS. Long-term continuation of Levetiracetam in patients with refractory epilepsy. Neurology 2001;56:1772-1774 - Krauss GL, Abou-khalil B, Sheth SG. Efficacy of levetiracetam for treatment fo drug-resistant generalised epilepsy. Epilepsia 2001;42(suppl 7):181 - Krauss GL, Betts T, Abou-Khalil B, Bergey G, Yarrow H, Miller A. Levetiracetam treatment of idiopathic generalised epilepsy. Seizure 2003;12:617-620
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• - Madeja M., Margineanu D.G., Gorji A., Siep E., Boerrigter P., Klitgaard H., Et Al. Reduction Of Voltage-Operated Potassium Currents By Levetiracetam: A Novel Antiepileptic Mechanism Of Action? - Neuropharmacology Oct-2003. 45(5):661-671. - Margineau D. G., Klitgaard Henrik Levetiracetam - Mechanism of action - Antiepilectic drugs, 5th edition. Edited by R.H. Levy, R.H. Mattson, B.S. Meldrum, and E.Perucca. Philadelphia: Lippincott Williams & Wilkins, 2002 - Margineau DG, Klitgaard H Inhibition of neural hyperynchrony in vitro differentiates levetiracetam fro classical antiepileptic drugs Pharmacol. Research 2000; 42(4): 281-285 - Marson AG, Hutton JL, Leach JP. Levetiracetam, Oxcarbazepine, Remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001;46:259-270
• - Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38:859-880 - Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Magnus L. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizure in an open-label community-based study. Epilepsy Res 2003;54:153-161 - Niespodziany I, Klitgaard H, Margineau DG Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices Neuropharmaology Neuroreport 2003; vol14(9): 1273-1276 - Noyer M, Gillard M, Magagne A., et al. The novel antiepileptic drug levetiracetam (ucb L059) appears o act via a specific binding site in CNS membranes. Eur J Pharmacol 1995 ; 286 : 137-146 - Patsalos PN Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol. Ther 2000; 83: 77-85 - Patsalos PN The pharmacokinetic characteristics of levetiracetam. Method Find. Exp. Clinic Pharmacol. 2003; 25: 123-129
• - Perucca E, Johannessen SI The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come? Epileptic Disorder 2003; 5(suppl 1):S17-S26 - Perucca E. Pharmacokinetics. In:Engel J Jr, Pedley TA Epilepsy-A comprehensive Textbook. New York: Raven Press 1997:1131-1153 - Radtke RA Pharmacokinetics of levetiracetam Epilepsia 2001; 42(Suppl 4):24-7 - Raguenau-Majlessi I, Levy RH, Meyerhoff C Lack of effect of repeated administration of levetiracetam on the pharmacodynamics and pharmakinetic profile of warfarin Epilepsy Res 2001; 47: 55-63 - Rigo JM, Hans G, Nguyen L, et al. The antiepileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA - and Glycine-gated current. Br J Pharmacol 2002; 136:659-72 - Sadek AH, Fix A, French J. Levetiracetam related behavioural adverse events: a post-marketing study. Epilepsia, 2002;43S8:151
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Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Anticipated): June 1, 2009
• Study Completion (Anticipated): June 1, 2009

Study Registration Dates

• First Submitted: October 11, 2007
• First Submitted That Met QC Criteria: October 11, 2007
• First Posted (Estimate): October 12, 2007

Study Record Updates

• Last Update Posted (Estimate): May 30, 2008
• Last Update Submitted That Met QC Criteria: May 26, 2008
• Last Verified: May 1, 2008

More Information

Terms related to this study

• Keywords: post stroke epileptic late onset seizures
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Stroke; Epilepsy; Seizures; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anticonvulsants; Sodium Channel Blockers; Antimanic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nootropic Agents; Levetiracetam; Carbamazepine
• Other Study ID Numbers: EpIc 1151