Study on the Treatment of Elderly Patients With Older and Newer Antiepileptic Drugs (STEP-ONE)

This study has been completed.
Sponsor:
Collaborator:
UCB Pharma GmbH
Information provided by (Responsible Party):
Konrad J. Werhahn, Johannes Gutenberg University Mainz
ClinicalTrials.gov Identifier:
NCT00438451
First received: February 21, 2007
Last updated: January 24, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Focal Epilepsy
Drug: Levetiracetam
Drug: Carbamazepine
Drug: Lamotrigine
Phase 4

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

Resource links provided by NLM:


Further study details as provided by Johannes Gutenberg University Mainz:

Primary Outcome Measures:
  • 58-week Retention Rate Measured by the Number of Drop Outs Due to Adverse Events or Seizures From Day 1 of Treatment [ Time Frame: 58 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to Drop Out [ Time Frame: 58 weeks ] [ Designated as safety issue: No ]
    number of days between randomization and premature discontinuation of the study

  • Percentage of Patients Remaining Seizure-free at Week 30 (Visit 4) [ Time Frame: Week 30 ] [ Designated as safety issue: No ]
    Percentage of patients experiencing no seizures until week 30 (Visit 4) and did not discontinue the study until week 30.

  • Percentage of Patients Remaining Seizure Free at Week 58 (Visit 6) [ Time Frame: week 58 ] [ Designated as safety issue: No ]
    Percentage of patients experiencing no seizures until week 58 (Visit 6) and did not discontinue the study until week 58.

  • The Time (in Days) to First Break-through Seizure (From Day 1 of Treatment) [ Time Frame: over the whole duration of 58 weeks ] [ Designated as safety issue: No ]
  • The Absolute Seizure Frequency During the Maintenance Phase (Weeks 7 - 58) [ Time Frame: over 52 weeks ] [ Designated as safety issue: No ]

    Seizure frequency was assessed by investigators in the CRF at the Visits V3, V4, V5 and V6.

    The absolute seizure frequency during the maintenance phase was defined as the sum of those entries.


  • Proportion of Seizure-free Days During the Maintenance Phase for Subjects Who Enter the Maintenance Phase [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • QOLIE-31 (Quality Of Life In Epilepsy) Results at V6 [ Time Frame: 58 weeks, final visit ] [ Designated as safety issue: No ]
    The QOLIE-31 is a 31 item score that measures the quality of life in epilepsy (each item with a range of 0 to 100). There are 7 sub-scores seizure worry (items 11,21,22,23,25), overall quality of life (items 1,14), emotional well-being (items 3,4,5,7,9), energy/fatigue (items 2,6,8,10), cognitive functioning (items 12,15,16,17,18,26), medication effects (items 24,29,30) and social functioning (13,19,20,27,28). These scores were combined to a total score by Total score = seizure worry*0.08 + overall quality of life*0.14 + emotional well-being*0.15 + energy/fatigue*0.12 + cognitive functioning*0.27 + medication effects*0.03 + social functioning*0.21 For all scores, higher values indicate better quality of life. Each score has a possible range from 0 to 100.

  • Portland Neurotoxicity Scale (PNS) at V6 [ Time Frame: at week 58 ] [ Designated as safety issue: No ]

    The PNS is a 15-item scale. Each item can be scored from 1 to 9. There are a total score (includes all items, range:15 to 135) and two subscores: The cognitive toxicity subscore (10 items: Energy Level, Memory, Interest, Concentration, Forgetfulness, Sleepliness, Moodiness, Alertness, Attention Span, Motivation, range:10 to 90) and the somatomoto subscore (5 items: Vision, Walking, Coordination, Tremor, Speech, range:5-45). The score is calculated by taking the mean of all non-missing values times the number of items.

    Lower values indicate better quality of life.


  • Results of Cognitive Testing (EpiTrack© by UCB) - Score at V6 [ Time Frame: week 58 ] [ Designated as safety issue: No ]
    EPITrack-Score shows the performance of attention and executive functions. Higher values indicate a better performance. The results of EPITrack Score ranges between 7 and 45.

  • Results of Cognitive Testing (EpiTrack© by UCB) - Categories at V6 [ Time Frame: 58 weeks ] [ Designated as safety issue: No ]

    Evaluation of current testing at V6:

    ≥29 score points: Inconspicuous; 26 to 28 score points: Borderline;

    ≤25 score points: Impaired


  • Results of Cognitive Testing (EpiTrack© by UCB) - Changes to Baseline (V0) at Week 58 (V6) [ Time Frame: week 58 ] [ Designated as safety issue: No ]

    Evaluation of Changes

    Changes in the EpiTrack® Score were categorized as follows:

    ≥5 score points: Improved;

    -3 to 4 score points: Unchanged;

    ≤-4 score points: Worsened



Enrollment: 361
Study Start Date: January 2007
Study Completion Date: August 2011
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Levetiracetam
Levetiracetam
Drug: Levetiracetam
LEV 250 mg capusles: week 1 and 2 0-0-1, week 3 and 4 1-0-1, week 5: 1-0-2, week 6: 2-0-2. Patients may take 2 to 12 per day (500 - 3000 mg)during maintenance.
Active Comparator: Carbamazepine
Carbamazepine
Drug: Carbamazepine
CBZ 100 mg capusles: week 1 and 2: 0-0-1, week 3 and 4: 1-0-1, week 5: 1-0-2, week 6: 2-0-2. Patients may take 2 to 12 per day (200 - 1200 mg) during maintenance depending on tolerance and efficacy.
Active Comparator: Lamotrigine
Lamotrigine
Drug: Lamotrigine
LTG 25 mg encapsulated: week 1 and 2: 0-0-1, week 3 and 4: 1-0-1, week 5: 1-0-2, week 6: 2-0-2. Patients may take 2 to 12 caps. per day (50 - 300 mg)during maintenance depending on tolerance and efficacy.

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).

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00438451

Locations
Germany
Department of Neurology, University of Mainz Medical Centre
Mainz, Germany, 55101
Sponsors and Collaborators
Johannes Gutenberg University Mainz
UCB Pharma GmbH
Investigators
Study Chair: Konrad J Werhahn, MD Johannes Gutenberg University, Department od Neurology
Study Director: Günter Kraemer, MD Swiss Epilepy Centre
Study Director: Eugen Trinka, MD Medical University of Salzburg, Department of Neurology, Austria
  More Information

Publications:
Responsible Party: Konrad J. Werhahn, Prof of Neurology, Head Section on Epilepsy, Johannes Gutenberg University Mainz
ClinicalTrials.gov Identifier: NCT00438451     History of Changes
Other Study ID Numbers: STEPONE05, ISRCTN: 94839639, EudraCT Number:2005-003324-19
Study First Received: February 21, 2007
Results First Received: September 24, 2012
Last Updated: January 24, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Austria: Agency for Health and Food Safety
Switzerland: Swissmedic

Keywords provided by Johannes Gutenberg University Mainz:
elderly
focal epilepsy
anticonvulsive
treatment
levetiracetam
lamotrigine
carbamazepine

Additional relevant MeSH terms:
Epilepsy
Epilepsies, Partial
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lamotrigine
Etiracetam
Anticonvulsants
Carbamazepine
Piracetam
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Nootropic Agents
Neuroprotective Agents
Protective Agents
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs

ClinicalTrials.gov processed this record on September 30, 2014