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

• ClinicalTrials.gov Identifier: NCT00542802
• Recruitment Status: Unknown
• First Posted: October 12, 2007
• Last Update Posted: May 30, 2008
• Sponsor: Scienze Neurologiche Ospedaliere
• Information provided by: Scienze Neurologiche Ospedaliere

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 (Clinical Trial)
• Estimated 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: September 2007
• Estimated Primary Completion Date: June 2009
• Estimated Study Completion Date: June 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

Outcome Measures

Primary Outcome Measures :

1. number of patients free from post stroke recurrent crisis [ Time Frame: one year ]

Secondary Outcome Measures :

1. To compare retention time of LEV vs CBZ since first intake throughout treatment period [ Time Frame: one year ]
2. To compare time to second seizure in both treatments. [ Time Frame: one year ]
3. 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 ]
4. evaluate EEG changes as compared with baseline with that obtained at the end of treatment period [ Time Frame: one year ]
5. To compare seizure frequency in levetiracetam and carbamazepine groups throughout treatment period [ Time Frame: one year ]
6. To evaluate the safety of levetiracetam versus carbamazepine throughout the treatment period [ Time Frame: one year ]

Eligibility Criteria

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

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

Contacts and Locations

Contacts

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

Contact: Sara Papetti; 0382 530676 ext +39; spapetti@gbpharmaservices.it

Locations

Italy

Ospedale S. Giacomo; Not yet recruiting

Novi Ligure, AL, Italy, 15057

Principal Investigator: MARCO AGUGGIA

Ospedale S. Croce E Carle; Not yet recruiting

Cuneo, CN, Italy, 12100

Principal Investigator: ENZO GRASSO

Ospedale S. Martino; Recruiting

Genova, GE, Italy, 16132

Principal Investigator: GIOVANNI REGESTA

Istituto Clinico Humanitas; Recruiting

Rozzano, MI, Italy, 20089

Principal Investigator: GIUSEPPE MICIELI

USL 2 Ospedale B.G. Villa; Not yet recruiting

Città della Pieve, PG, Italy, 06062

Principal Investigator: STEFANO RICCI

Ospedale Civile San Giovanni Battista di Foligno; Recruiting

Foligno, PG, Italy

Principal Investigator: Pierluigi BRUSTENGHI

Ospedale Santa Maria della Misericordia; Not yet recruiting

Sant'Andrea delle Fratte, PG, Italy, 06131

Principal Investigator: ANNA CANTISANI

Istituto Neurologico C. Mondino; Not yet recruiting

Pavia, PV, Italy, 27100

Contact: Anna Cavallini, doctor

Principal Investigator: Anna Cavallini, doctor

Ospedale Guzzardi; Recruiting

Vittoria, RG, Italy, 97019

Principal Investigator: FRANCESCO IEMOLO

Ospedale Di Portogruaro; Recruiting

Portogruaro, VE, Italy, 30026

Principal Investigator: SEBASTIANO D'ANNA

Ospedale Civile; Recruiting

Vibo Valentia, VV, Italy, 89900

Principal Investigator: domenico consoli, doctor

Policlinico Umberto I; Not yet recruiting

Ancona, Italy, 60020

Principal Investigator: LEANDRO PROVINCIALI

Ospedale A. Perrino; Recruiting

Brindisi, Italy, 72100

Principal Investigator: BRUNO PASSARELLA

Ospedale Cannizzaro; Not yet recruiting

Catania, Italy, 95126

Principal Investigator: ERMINIO COSTANZO

Ospedale San Martino; Recruiting

Genova, Italy

Principal Investigator: carlo GANDOLFO

Ospedale Civile Imperia ASL 1; Recruiting

Imperia, Italy, 18100

Principal Investigator: Carlo SERRATI

Ospedale A. Cardarelli-; Recruiting

Napoli, Italy, 80131

Principal Investigator: MAURO PAGLIUCA, Dr.

Ospedale Cardarelli; Not yet recruiting

Napoli, Italy, 80131

Principal Investigator: VINCENZO ROSSI

Ospedale Civico; Not yet recruiting

Palermo, Italy, 90100

Principal Investigator: ERALDO NATALE'

Osp. Guglielmo da saliceto; Recruiting

Piacenza, Italy, 29100

Principal Investigator: DONATA GUIDETTI

Arcispedale S. Maria Nuova; Recruiting

Reggio Emilia, Italy, 42100

Principal Investigator: Romana RIZZI

Ospedale SS. Annunziata - Ospedale Civile; Recruiting

Taranto, Italy

Principal Investigator: saverio INTERNO'

Ospedale Molinette-Università di Torino; Recruiting

Torino, Italy

Principal Investigator: Dario GIOBBE

Azienda Ospedaliera Universitaria Trieste; Recruiting

Trieste, Italy, 34149

Principal Investigator: FABIO CHIODO GRANDI

Sponsors and Collaborators

Scienze Neurologiche Ospedaliere

Investigators

• Principal Investigator: domenico consoli, doctor; Ospedale Civile Vibo Valentia

More Information

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Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Coté 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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• Responsible Party: Dr. Domenico Consoli, Scienze Neurologiche Ospedaliere
• ClinicalTrials.gov Identifier: NCT00542802 History of Changes
• Other Study ID Numbers: EpIc 1151
• First Posted: October 12, 2007
• Last Update Posted: May 30, 2008
• Last Verified: May 2008

Keywords provided by Scienze Neurologiche Ospedaliere:

post stroke epileptic late onset seizures

Additional relevant MeSH terms:

Stroke; Seizures; Epilepsy; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Neurologic Manifestations; Signs and Symptoms; Carbamazepine; Levetiracetam; Anticonvulsants; Nootropic Agents; Antimanic Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs; Psychotropic Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 Enzyme Inducers