Levetiracetam Versus Carbamazepine in Post-Stroke Late Onset Crisis

Condition(s) targeted: Epileptic Seizures; Stroke

Intervention: Levetiracetam (Drug); Carbamazepine (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Scienze Neurologiche Ospedaliere

Official(s) and/or principal investigator(s):
domenico consoli, doctor, Principal Investigator, Affiliation: Ospedale Civile Vibo Valentia

Overall contact:
Domenico Consoli, Doctor, Ext: +39, Email: domco@tiscali.it

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.

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

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment

Primary outcome: number of patients free from post stroke recurrent crisis

Secondary outcome:

To compare retention time of LEV vs CBZ since first intake throughout treatment period

To compare time to second seizure in both treatments.

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

evaluate EEG changes as compared with baseline with that obtained at the end of treatment period

To compare seizure frequency in levetiracetam and carbamazepine groups throughout treatment period

To evaluate the safety of levetiracetam versus carbamazepine throughout the treatment period

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Domenico Consoli, Doctor, Ext: +39, Email: domco@tiscali.it

Azienda Ospedaliera Universitaria Trieste, TRIESTE 34149, Italy; Recruiting
FABIO CHIODO GRANDI, Principal Investigator

Policlinico Umberto I, ANCONA 60020, Italy; Not yet recruiting
LEANDRO PROVINCIALI, Principal Investigator

Osp. Guglielmo da saliceto, PIACENZA 29100, Italy; Recruiting
DONATA GUIDETTI, Principal Investigator

Ospedale A. Cardarelli-, NAPOLI 80131, Italy; Recruiting
MAURO PAGLIUCA, Dr., Principal Investigator

Ospedale A. Perrino, BRINDISI 72100, Italy; Recruiting
BRUNO PASSARELLA, Principal Investigator

Ospedale Cannizzaro, CATANIA 95126, Italy; Not yet recruiting
ERMINIO COSTANZO, Principal Investigator

Ospedale Cardarelli, NAPOLI 80131, Italy; Not yet recruiting
VINCENZO ROSSI, Principal Investigator

Ospedale Civico, PALERMO 90100, Italy; Not yet recruiting
ERALDO NATALE', Principal Investigator

Arcispedale S. Maria Nuova, REGGIO EMILIA 42100, Italy; Recruiting
Romana RIZZI, Principal Investigator

Ospedale Civile Imperia ASL 1, IMPERIA 18100, Italy; Recruiting
Carlo SERRATI, Principal Investigator

Ospedale Molinette-Università di Torino, TORINO, Italy; Recruiting
Dario GIOBBE, Principal Investigator

Ospedale SS. Annunziata - Ospedale Civile, Taranto, Italy; Recruiting
saverio INTERNO', Principal Investigator

Ospedale San Martino, GENOVA, Italy; Recruiting
carlo GANDOLFO, Principal Investigator

Ospedale S. Giacomo, NOVI LIGURE, AL 15057, Italy; Not yet recruiting
MARCO AGUGGIA, Principal Investigator

Ospedale S. Croce E Carle, CUNEO, CN 12100, Italy; Not yet recruiting
ENZO GRASSO, Principal Investigator

Ospedale S. Martino, GENOVA, GE 16132, Italy; Recruiting
GIOVANNI REGESTA, Principal Investigator

Istituto Clinico Humanitas, ROZZANO, MI 20089, Italy; Recruiting
GIUSEPPE MICIELI, Principal Investigator

Ospedale Santa Maria della Misericordia, Sant'Andrea delle Fratte, PG 06131, Italy; Not yet recruiting
ANNA CANTISANI, Principal Investigator

USL 2 Ospedale B.G. Villa, Città della Pieve, PG 06062, Italy; Not yet recruiting
STEFANO RICCI, Principal Investigator

Ospedale Civile San Giovanni Battista di Foligno, FOLIGNO, PG, Italy; Recruiting
Pierluigi BRUSTENGHI, Principal Investigator

Istituto Neurologico C. Mondino, Pavia, PV 27100, Italy; Not yet recruiting
Anna Cavallini, doctor
Anna Cavallini, doctor, Principal Investigator

Ospedale Guzzardi, VITTORIA, RG 97019, Italy; Recruiting
FRANCESCO IEMOLO, Principal Investigator

Ospedale Di Portogruaro, PORTOGRUARO, VE 30026, Italy; Recruiting
SEBASTIANO D'ANNA, Principal Investigator

Ospedale Civile, Vibo Valentia, VV 89900, Italy; Recruiting
domenico consoli, doctor, Principal Investigator

Related publications:

Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol. 2002 Feb;59(2):195-201. Review.

Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet. 2000 Apr 22;355(9213):1441-6. Review.

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. 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.

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.

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.

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.

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.

Sung CY, Chu NS. Epileptic seizures in thrombotic stroke. J Neurol. 1990 Jun;237(3):166-70.

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Starting date: September 2007
Ending date: June 2009
Last updated: May 26, 2008