Study on the Treatment of Elderly Patients With Older and Newer Antiepileptic Drugs

Condition(s) targeted: Focal Epilepsy

Intervention: Levetiracetam (Drug); Carbamazepine (Drug); Lamotrigine (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Johannes Gutenberg University Mainz

Official(s) and/or principal investigator(s):
Konrad J Werhahn, MD, Study Chair, Affiliation: Johannes Gutenberg University, Department od Neurology
Günter Kraemer, MD, Study Director, Affiliation: Swiss Epilepy Centre
Eugen Trinka, MD, Study Director, Affiliation: Medical University of Salzburg, Department of Neurology, Austria

In this clinical trial patients with newly diagnosed focal epilepsy aged 60 years or older receive three different antiepileptic drugs in a double-blind, randomized design over a period of 58 weeks. All drugs are licensed for the treatment of epilepsy. The primary endpoint of this study will be retention rate at 58-weeks, since it reflects both efficacy and tolerability.

Official title: A Multicentre, Double-blind, Randomized, Phase IV Clinical Trial Comparing the Safety, Tolerability and Efficacy of Levetiracetam Versus Lamotrigine and Carbamazepine in the Oral Antiepileptic Therapy of Newly Diagnosed Elderly Patients With Focal Epilepsy.

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: 58-week Retention Rate Measured by the Number of Drop Outs Due to Adverse Events or Seizures From Day 1 of Treatment

Secondary outcome:

Time to Drop Out

Percentage of Patients Remaining Seizure-free at Week 30 (Visit 4)

Percentage of Patients Remaining Seizure Free at Week 58 (Visit 6)

The Time (in Days) to First Break-through Seizure (From Day 1 of Treatment)

The Absolute Seizure Frequency During the Maintenance Phase (Weeks 7 - 58)

Proportion of Seizure-free Days During the Maintenance Phase for Subjects Who Enter the Maintenance Phase

QOLIE-31 (Quality Of Life In Epilepsy) Results at V6

Portland Neurotoxicity Scale (PNS) at V6

Results of Cognitive Testing (EpiTrack© by UCB) - Score at V6

Results of Cognitive Testing (EpiTrack© by UCB) - Categories at V6

Results of Cognitive Testing (EpiTrack© by UCB) - Changes to Baseline (V0) at Week 58 (V6)

Detailed description: Indication: Focal Epilepsy Objectives: To evaluate the tolerability and efficacy of levetiracetam (LEV) in newly diagnosed elderly patients (aged 60 yrs or above) with focal epilepsy compared to lamotrigine (LTG) or carbamazepine slow release (CBZ). Primary Outcome: The primary outcome will be the 58-week retention rate measured by the number of drop outs due to adverse events or seizures from day 1 of treatment. Secondary Outcome: Proportion of patients remaining seizure-free at week 30 (Visit 4); proportion of patients remaining seizure free at week 58 (Visit 6); the time (in days) to first break-through seizure (from day 1 of treatment); the absolute seizure frequency during the maintenance (over 52 weeks) phase; proportion of seizure-free days during the maintenance phase for subjects who enter the maintenance phase; the frequency of adverse events (from day 1 of treatment); QOLIE-31 results at V6; Portland Neurotoxicity scale at V6; results of cognitive testing (EpiTrack© by UCB). Trial Design: This is a randomized, double-blind, multicenter Phase IV study using a parallel group design with three treatment groups. The study will consist of a 6-week titration-phase and a 52-week maintenance phase. Patients who successfully complete the trial (final visit, V6) will be unblinded and offered either to continue on their current drug or be changed to an alternative antiepileptic drug (AED) treatment of choice. Population: Patients aged 60 years or above with new onset focal epilepsy i. e. either at least one epileptic seizure in the last 6 months and focal epileptiform discharges on EEG or a relevant lesion on CT/MRI or a total of 2 epileptic seizures, one of which occurring in the last 6 months prior inclusion. Patients with acute (< 2 weeks) symptomatic epileptic seizures due to acute brain abnormalities (i. e. haemorrhage or cerebral infarct), or contraindications against any of the drugs in trial will be excluded. Sample Size: 360 patients to be included, 120 patients per treatment arm. Investigational Medicinal Product(s): Levetiracetam, lamotrigine, carbamazepine-slow release Trial Duration and Dates: Duration of treatment: 6 weeks titration phase, 52 weeks maintenance phase. Follow up: At the end of trial subjects will be unblinded and may choose to continue on the medication or taper the trial medication and be treated with an alternative drug at the investigators discretion. The patient will receive a dosing schedule and a referral letter for his/her physician. Duration of trial: approximately 2 years. Start of recruitment: January 2007 Projected number of centres: 75 Number of countries: 3 (Germany, Switzerland, Austria).

Minimum age: 60 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age 60 yrs or above.

- New onset focal epilepsy i. e. either at least one epileptic seizure in the last 6

months and focal epileptiform discharges on EEG or a relevant lesion on CT/MRI or at least 2 epileptic seizures, one of which occurring in the last 6 months prior inclusion.

- No previous AED treatment, except for a period not longer than 4 weeks prior to

inclusion (V0).

- Ability of subject to understand verbal and written instructions, to comply with all

study requirements, and to comprehend character and individual consequences of the clinical trial.

- Written informed consent before enrolment in the trial.

Exclusion Criteria:

- Acute symptomatic epileptic seizures occurring acutely within a 2 week period after

the onset of an acute illness such as cerebral haemorrhage, cerebral infarct, rapid progressive malignancy or other acute brain abnormalities (i. e. encephalitis, hypoxic brain damage, trauma, metabolic derangement, following brain surgery).

- Dementia (as defined by history)

- Renal insufficiency as defined by GFR < 50 mL/min.

- Increased liver enzymes (GOT, GPT, gGT) or increased bilirubin ≥ 2-fold the upper

limit of normal (ULN).

- Pre-treatment with valproic acid within the four weeks prior inclusion (V0).

- Contraindication against or history of hypersensitivity to any of the investigational

medicinal products or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal products.

- Participation in other clinical trials and observation period of competing trials

within the last 2 months, respectively.

- History of drug or alcohol abuse within the last 2 years.

- Medical condition which interferes with the participation in the trial according to

the opinion of the investigator.

- Patients with life expectancy < 1 year due to malignant disease

- Psychiatric morbidity requiring legal guardianship.

Department of Neurology, University of Mainz Medical Centre, Mainz 55101, Germany

Related publications:

Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, Spitz M, Frederick T, Towne A, Carter GS, Marks W, Felicetta J, Tomyanovich ML; VA Cooperative Study 428 Group. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology. 2005 Jun 14;64(11):1868-73.

Brodie MJ, Chadwick DW, Anhut H, Otte A, Messmer SL, Maton S, Sauermann W, Murray G, Garofalo EA; Gabapentin Study Group 945-212. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia. 2002 Sep;43(9):993-1000.

Starting date: January 2007
Last updated: January 24, 2013