Official Title: “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 Type: Interventional

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

Study Primary Completion Date: June 2009

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.

Intervention(s) in this Clinical Trial

• 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
• 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

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: LEV
  • Levetiracetam
• Active Comparator: CAR
  • Carbamazepina

Primary Measures

• number of patients free from post stroke recurrent crisis
  • Time Frame: one year
    Safety Issue?: No

Secondary Measures

• To compare retention time of LEV vs CBZ since first intake throughout treatment period
  • Time Frame: one year
    Safety Issue?: No
• To compare time to second seizure in both treatments.
  • Time Frame: one year
    Safety Issue?: No
• 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
  • Time Frame: one year
    Safety Issue?: No
• evaluate EEG changes as compared with baseline with that obtained at the end of treatment period
  • Time Frame: one year
    Safety Issue?: No
• To compare seizure frequency in levetiracetam and carbamazepine groups throughout treatment period
  • Time Frame: one year
    Safety Issue?: No
• To evaluate the safety of levetiracetam versus carbamazepine throughout the treatment period
  • Time Frame: one year
    Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Scienze Neurologiche Ospedaliere

Overall Clinical Trial Officials and Contacts

domenico consoli, doctor Principal Investigator Ospedale Civile Vibo Valentia  

Overall Contact: Domenico Consoli, Doctor  domco@tiscali.it

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00542802

Study ID Number: EpIc 1151

ClinicalTrials.gov Identifier: NCT00542802

Health Authority: Italy: Ethics Committee