EpIc: Levetiracetam Versus Carbamazepine in Post-Stroke Late Onset Crisis

Sponsor

Scienze Neurologiche Ospedaliere (Other)

Overall Status

Unknown status

CT.gov ID

NCT00542802

Collaborator

(none)

630

Enrollment

Locations

Arms

Duration (Months)

26.3

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Epileptic Seizures Stroke	Drug: Levetiracetam Drug: Carbamazepine	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

630 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2007

Anticipated Primary Completion Date :

Jun 1, 2009

Anticipated Study Completion Date :

Jun 1, 2009

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

number of patients free from post stroke recurrent crisis [one year]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale S. Giacomo	Novi Ligure	AL	Italy	15057
2	Ospedale S. Croce E Carle	Cuneo	CN	Italy	12100
3	Ospedale S. Martino	Genova	GE	Italy	16132
4	Istituto Clinico Humanitas	Rozzano	MI	Italy	20089
5	USL 2 Ospedale B.G. Villa	Città della Pieve	PG	Italy	06062
6	Ospedale Civile San Giovanni Battista di Foligno	Foligno	PG	Italy
7	Ospedale Santa Maria della Misericordia	Sant'Andrea delle Fratte	PG	Italy	06131
8	Istituto Neurologico C. Mondino	Pavia	PV	Italy	27100
9	Ospedale Guzzardi	Vittoria	RG	Italy	97019
10	Ospedale Di Portogruaro	Portogruaro	VE	Italy	30026
11	Ospedale Civile	Vibo Valentia	VV	Italy	89900
12	Policlinico Umberto I	Ancona		Italy	60020
13	Ospedale A. Perrino	Brindisi		Italy	72100
14	Ospedale Cannizzaro	Catania		Italy	95126
15	Ospedale San Martino	Genova		Italy
16	Ospedale Civile Imperia ASL 1	Imperia		Italy	18100
17	Ospedale A. Cardarelli-	Napoli		Italy	80131
18	Ospedale Cardarelli	Napoli		Italy	80131
19	Ospedale Civico	Palermo		Italy	90100
20	Osp. Guglielmo da saliceto	Piacenza		Italy	29100
21	Arcispedale S. Maria Nuova	Reggio Emilia		Italy	42100
22	Ospedale SS. Annunziata - Ospedale Civile	Taranto		Italy
23	Ospedale Molinette-Università di Torino	Torino		Italy
24	Azienda Ospedaliera Universitaria Trieste	Trieste		Italy	34149