Levetiracetam Versus Carbamazepine in Post-Stroke Late Onset Crisis

Stroke Clinical Trial

— EpIc  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00542802
• Other study ID #: EpIc 1151
• Status: Recruiting
• Phase: Phase 3
• First received: October 11, 2007
• Last updated: May 26, 2008
• Start date: September 2007
• Est. completion date: June 2009

Study information

• Verified date: May 2008
• Source: Scienze Neurologiche Ospedaliere
• Contact: Domenico Consoli, Doctor
• Email: domco[@]tiscali.it
• Is FDA regulated: No
• Health authority: Italy: Ethics CommitteeItaly: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 630
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Epilepsy
• Epileptic Seizures
• Stroke

Intervention

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
• 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

Locations

Country	Name	City	State
Italy	Policlinico Umberto I	Ancona
Italy	Ospedale A. Perrino	Brindisi
Italy	Ospedale Cannizzaro	Catania
Italy	USL 2 Ospedale B.G. Villa	Città della Pieve	PG
Italy	Ospedale S. Croce E Carle	Cuneo	CN
Italy	Ospedale Civile San Giovanni Battista di Foligno	Foligno	PG
Italy	Ospedale S. Martino	Genova	GE
Italy	Ospedale San Martino	Genova
Italy	Ospedale Civile Imperia ASL 1	Imperia
Italy	Ospedale A. Cardarelli-	Napoli
Italy	Ospedale Cardarelli	Napoli
Italy	Ospedale S. Giacomo	Novi Ligure	AL
Italy	Ospedale Civico	Palermo
Italy	Istituto Neurologico C. Mondino	Pavia	PV
Italy	Osp. Guglielmo da saliceto	Piacenza
Italy	Ospedale Di Portogruaro	Portogruaro	VE
Italy	Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Istituto Clinico Humanitas	Rozzano	MI
Italy	Ospedale Santa Maria della Misericordia	Sant'Andrea delle Fratte	PG
Italy	Ospedale SS. Annunziata - Ospedale Civile	Taranto
Italy	Ospedale Molinette-Università di Torino	Torino
Italy	Azienda Ospedaliera Universitaria Trieste	Trieste
Italy	Ospedale Civile	Vibo Valentia	VV
Italy	Ospedale Guzzardi	Vittoria	RG

Sponsors (1)

Lead Sponsor	Collaborator
Scienze Neurologiche Ospedaliere

Country where clinical trial is conducted

Italy, 

References & Publications (25)

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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

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- Shorvon SD, Van Rijckevorsel. A new antiepileptic drug Levetiracetam, a pyrrolidone recently licensed as an antiepileptic drug. J Neurol Neurosurg Psychiatry 2002 ;72: 426-429 - Smith K, Betts T, Pritchett L. Levetiracetam, a promising option for the treatment of juvenile myoclonic epilepsy. Epilepsia 2000;41(suppl1):39 - Van Rijckevorsel K. The " number needed to treat " with levetiracetam : comparison with the other new antiepileptic drugs. Seizure 2001;10:235-236 - Welty TE, Gidal BE, Ficker DM, Privitera MD. Levetiracetam: a different approach to the pharmacotherapy of epilepsy. The Annals of Pharmacotherapy 2002;36:296-304 - Zona C, Niespodziany I, Marchetti C, et al. Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Seizure 2001; 10: 279-86

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	number of patients free from post stroke recurrent crisis		one year	No
Secondary	To compare retention time of LEV vs CBZ since first intake throughout treatment period		one year	No
Secondary	To compare time to second seizure in both treatments.		one year	No
Secondary	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	No
Secondary	evaluate EEG changes as compared with baseline with that obtained at the end of treatment period		one year	No
Secondary	To compare seizure frequency in levetiracetam and carbamazepine groups throughout treatment period		one year	No
Secondary	To evaluate the safety of levetiracetam versus carbamazepine throughout the treatment period		one year	Yes