Effects of Keppra on Thinking, Emotions, and Balance in Elderly Healthy Volunteers
Condition: Epilepsy
MeSH terms: Epilepsy
Study type: Interventional

Summary: 
      Epilepsy is a common disorder with an incidence of about 6 per 1000. The incidence
      progressively increases above age 50. By age 75, the incidence is two to three fold compared
      with any age group. Unfortunately, older individuals are especially at risk to incur
      significant side effects to anti-epileptic drugs. A newer anti-epileptic drug may markedly
      improve seizure management in older individuals as it is removed by the kidneys and not the
      liver and does not interact with other medications. We expect it to be tolerated well in
      terms of effects on memory, thinking,balance, and walking. The current study assesses the
      side effects of levetiracetam in healthy volunteers aged 65 to 80. Use of healthy volunteers
      eliminates the effects of seizures on the outcome.
    

Detailed description: 
      III. INTRODUCTION:

      Background Antiepileptic Drugs And Cognitive Dysfunction Epilepsy is the most common
      debilitating neurologic disorder, with a prevalence of about 6/1000 in the general population
      (Hauser and Hesdorffer, 1990). Along with the disabling psychosocial and physical
      disadvantages that accompany epilepsy, medication concerns are frequently reported (Gilliam F
      et al. 1997). The majority of adverse events related to medications pertain to cognition
      (Baker GA et al. 1997).

      A variety of factors contribute to cognitive dysfunction in persons with epilepsy, one of
      which is treatment with antiepileptic drugs (AEDs). The effects of AEDs appear to display a
      dose dependent relationship to cognitive functioning. Even more striking adverse effects on
      cognition are found as a result of AED polytherapy. Evaluation of the cognitive effects of
      AEDs in patients with epilepsy can easily be confounded by seizure effects, underlying
      cerebral injury, genetic, factors, and chronic impact of living with seizures. To limit the
      confounding cognitive effects of epilepsy, investigators have examined the cognitive effects
      of AEDs in healthy volunteers. Meador et al. (1995) have presented data demonstrating mild
      untoward effects of three common first line AEDs in a group of young healthy adults employing
      a randomized, double-blind, incomplete block crossover design. More than one-half of the
      neurocognitive dependent variables exhibited AED effects when compared with non-drug
      baselines. Studies of newer drugs have shown variable impairment with gabapentin and
      lamotrigine showing less impairment compared to the older, first-line drugs and to
      topiramate.

      Epilepsy In The Elderly The incidence of epilepsy increases as age advances beyond 50. Indeed
      there is a two- to three-fold increase above the age of 75 years compared with any other age
      group (Ramsay et al. 2004). This special population is at increased risk for development of
      adverse events related to AED treatment as they are likely to have multiple medical
      conditions, take numerous concomitant medications, have different metabolic characteristics,
      and are more likely to suffer from neurologic conditions such as stroke and dementia. The
      elderly are more susceptible to cognitive impairment by AEDs. However, little is known of
      factors affecting health-related quality of life in senior adults with epilepsy (Martin et
      al., 2003)6. All older AEDs have clear pharmacokinetic disadvantages as they are liver
      metabolized with many known drug interactions.

      Levetiractam Levetiracetam was approved by the FDA in 1999 for the treatment of epilepsy.
      Levetiracetam was shown to be an effective pharmacologic treatment for refractory partial
      seizures in a number of large multicenter clinical trials (French, et al., 2001; Cramer et
      al., 2003; Morrell et al., 2003). The pharmacokinetic profile of levetiracetam has particular
      advantages over other anti-epileptic drugs. Pharmacologic advantages include low protein
      binding, renal clearance, and an absence of drug interactions (Perucca and Johannessen,
      2003.).

      For the older patient with epilepsy, levetiracetam is likely to offer an excellent
      alternative to other AEDs that are known to interact with other medications. Levetiracetam
      has performed favorably in adults with epilepsy (Ben-Menachem & Gilland, 2003; Morrell et
      al., 2003). The efficacy of levetiracetam has been demonstrated for epilepsy in older adults
      (Cramer et al. 2003; Kraemer & Edrich, 2001).

      Clinical experience suggests that Levetiracetam is a well-tolerated medication with minimal
      cognitive or sedative effects. Levetiracetam is a structural analogue of piracetam, a drug
      used as a nootropic (cognitive enhancing) agent in Europe. However, a recent
      placebo-controlled study of adjunctive levetiracetam therapy for intractable complex partial
      seizures showed several CNS adverse events more common than placebo, including somnolence,
      asthenia, and dizziness (Morrell et al., 2003). The occurrence of these specific cognitive
      adverse events were relatively modest ranging from one to seven per cent relative to placebo.
      Data detailing the cognitive and mood profile of levetiracetam in healthy older adults are
      limited. Kraemer and Edrich (2003) using pooled clinical trial data found no differences in
      the incidence of central nervous system events between elderly patients and younger adults in
      a large clinical trial. Similarly , the KEEPER trial found no difference in frequency of side
      effects to levetiracetam in younger verses adults over 65 (range 65 to>85) . The KEEPER trial
      was a phase IV study that has limited interpretability as it was open label (Ferrendelli et
      al., 2003). Clinical experience has been consistent in showing good tolerability in the
      elderly (French 2001 ;Cramer et al 2003a; Ferrendelli et al, 2003 ; Pryor and Ramsay, 2003 ;
      Ramsay et al,2003 ; Werz et al 2003 ; Alsaadi et al 2004). However, the neurocognitive and
      mood effects of levetiracetam in older adults have not yet been documented in well designed
      trials to specifically address this issue.

      Studies have demonstrated similar seizure-free rates for the second generation AEDs, with the
      main difference being their side effect profile. Evidenced based medicine requires data to
      support prescription practices, and we hypothesize that the current data will provide support
      for the use of levetiracetam in older adults with epilepsy. We predict no significant effects
      of the study drug on cognition.

      IV. STUDY OBJECTIVES AND ENDPOINTS Objective The primary objective of this study is to
      compare the effects of levetiracetam to placebo on neuropsychological and mood function in
      elderly healthy volunteers.

      Study Endpoints

        -  Neuropsychological evaluations of cognitive function, behavioral responses, speech, and
           mood (See Appendix 1)

        -  Early discontinuation for adverse events V. STUDY DESIGN General Description This is a
           randomized, double-blind, placebo controlled, crossover study of levetiracetam in
           healthy older adults. The study is divided into 6 phases, which will occur over a total
           of 14 weeks: Screen (-2 weeks), Randomization (0 weeks), First Drug Treatment Period (4
           weeks), Washout (2 weeks), Second Drug Treatment Period (4 weeks), and Post-Treatment (2
           weeks) (Appendix 2). Each Drug Treatment Period is further divided into the Titration,
           Maintenance, and Taper Phases. Following Screening, subjects will be randomized (1:1) to
           receive either levetiracetam or placebo the First Drug Treatment Period. After
           completion of this phase and the subsequent Washout, subjects will receive the alternate
           therapy in the Second Drug Treatment Period.

      Neuropsychological testing will be performed at screening, baseline, and during each
      maintenance phase. Each neuropsychological testing involves about two hours of pen and paper
      testing. A complete list of tests is given in Appendix 1.

      Enrollment will occur at University Hospitals of Cleveland, Department of Neurology.

      Study Population Inclusion Criteria

      A subject will be eligible for inclusion in this study only if all of the following criteria
      apply. A subject must:

        1. Provide a copy of their medical records from a primary care physician for the past year
           to assist in establishing the patient's current health status. The study physician will
           review PCP medical records to assure participants meet the study inclusion/exclusion
           criteria.

        2. Be a healthy adult age 65 to 80 years old. Healthy subjects are defined as individuals
           who are free from significant cardiac, pulmonary, gastrointestinal, hepatic, renal,
           hematological, neurological and psychiatric disease as determined by history and
           physical examination.

        3. Be, in the investigator's opinion, compliant, able to follow the investigator's
           instructions and visit the clinic on schedule, cooperative and reliable.

        4. Subjects must score within -1.0 standard deviations of the mean performance of healthy
           individuals on the neuropsychological tests at screen (week -2). Subjects must have a
           reading equivalency of 8th grade. Participants must also have a MMSE score of 28. (Bravo
           & Herbert, 1997; Crum et al., 1993). Finally, participants must score a 45 or better on
           the Berg Balance Test at screening (week -2) to be included in the study.

        5. Sign an informed consent.

        6. For participants living alone, provide the name and number of at least one friend or
           family member that study personnel may contact in the unlikely event that study
           personnel are unable to contact the patient by phone past 48 hours of a scheduled phone
           contact time which was not planned.

      Exclusion Criteria

      A subject will not be eligible for inclusion in this study if any of the following criteria
      apply. A subject must not:

        1. Have a history of any type of epilepsy.

        2. Be taking any concomitant medications that are or any concomitant medications that may
           alter cognitive function or mood.

        3. Have a current or past history of drug or alcohol abuse or dependence. Have a positive
           urine toxicology test at screen.

        4. Have a history and clinical finding of a progressive encephalopathy including CNS tumors
           of all types.

        5. Have a serious illness in the past month that may confound the interpretation of study
           results.

        6. Be on anticoagulation with warfarin.

        7. Have experienced a prior adverse reaction or hypersensitivity to either study medication
           or to related compounds.

        8. Be currently participating in another clinical study in which the subject will be
           exposed to an investigational or a non-investigational drug or device.

      Procedures to be performed and visit schedule Screening Clinic Visit 1(Visit 1, week -2): At
      screen, participating subjects will sign informed consent. Subjects will undergo exam to
      determine whether they qualify for participation in the study. Examination will include a
      complete physical and neurological examination, vital signs, neuropsychological assessment,
      MMSE, and Berg Balance Test. Neuropsychological assessment will require about 2 hours of pen
      and paper testing. Participants must score within -1.0 SD of the mean performance of age- and
      education-matched peers on each neuropsychological test. Participants must also not present
      on the physical or neurological exam with any exclusionary criteria Participants that meet
      the screening criteria will be invited back for the baseline visit (week 0). Subjects will be
      asked to bring with them at the baseline visit their medical records from their primary care
      physician and signed releases for their medical records will be obtained.

      Randomization (week 0): Subjects will be randomized to receive either levetiracetam or
      placebo.

      Baseline - Clinic Visit 2 (Visit 2, week 1): medical history, comprehensive physical and
      neurological examination, vital signs. Neuropsychological assessment will be completed. This
      involves pen and paper testing over about two hours. Laboratory evaluation will be performed
      including complete blood count, basic metabolic sceen including creatinine, hepatic function,
      coagulation parameters, and urine toxicology screen.

      Study Drugs and Dosages KEPPRA (levetiracetam) 500 mg scored tablets will be supplied with
      matching placebo tablets. The dosage of levetiracetam will be about 1000 mg per day to be
      consistent with clinical experience with the elderly.

      Titration During the Titration Phase of each Drug Treatment Period, doses of levetiracetam
      (or placebo) will be started at 250 mg twice a day (500 mg total daily dose) and increased
      over a period of two weeks to a target maintenance dose of 1000mg/day in divided dose,
      according to the dosing schedule outlined in the table that follows (Appendix 2). Upon
      achieving the target maintenance dose, subjects will receive this dose for one week during
      the Maintenance Phase. Following the Maintenance Phase, study drug will be tapered off over a
      period of one week and maintained off drug for one week (weeks 6 through 7) (washout period).
      The second treatment period will then begin (6 weeks).

      Clinic Visit 3 (week 5) will occur at the end of the drug maintenance phase of the first Drug
      Treatment Period and include neurological examination, vital signs, and blood draw for drug
      serum concentration requiring about 60 minutes. Visit 2 will also include neuropsychological
      testing taking about two hours.

      Clinic Visit 4 (week 7 - baseline 2) will occur at the end of the first drug washout and will
      involve a neurological and physical examination taking about 45-60 minutes. Subjects will
      complete Neuropsychological Assessment. Participants will then begin the second treatment
      phase.

      Clinic Visit 5 (week 11) will occur at the end of the drug maintenance phase of the second
      drug treatment period and will also include neurological examination, vital signs, and blood
      draw for drug serum concentration taking about 60 minutes. Visit 5 will also include
      neuropsychological testing taking about two hours.

      Clinic Visit 6 (Final visit, week 13): will occur after washout of the second drug and will
      again involve comprehensive physical and neurologic examination taking 45 to 60 minutes.

      Phone calls will be made weeks 2, 3, 4, 6, 8, 9, and 12 to check on medication use and side
      effects for study participants that have a spouse or caregiver at home. Participants that
      report that they live alone will be called 3 times weekly during the study period (e.g.,
      Monday, Wednesday, Friday).

      VII. DATA ANALYSIS

      A power analysis was conducted to determine the minimum sample size needed to detect changes
      on neuropsychological test scores with a formula for repeated measures of continuous data:

      Although the within subject standard deviation (the standard deviation of repeated
      observations in the same individual) is unknown for studies with levetiracetam, data from
      similar research with anti-epileptic medications and published normative data for these tests
      suggests the within subject standard deviation varies from a standardized 0.1 to 0.6 units. A
      minimum power of 0.80 ( A minimum detectable difference in neuropsychological tests scores
      was set at a 0.5 units (a half a standard deviation in change for a neuropsychological test
      score). A standardized measure of mean difference was selected as the raw scores of
      neuropsychological instruments vary, and converting raw scores to standard scores allow all
      test scores to be compared using a common metric. Based on a two-tailed significance of 0.05,
      the minimum N needed is 18 subjects. With 20 participants, assuming a within subject standard
      deviation of 0.5 units, the minimum detectable difference will be 0.467 standard deviation
      units (slightly less than a ½ a standard deviation of change). It should be noted that for
      several neuropsychological tests the within subject change is less than 0.2 SD units. With a
      smaller within subject SD, and using the same parameters above, N = 20 yields a minimum
      detectable difference of 0.187 standard deviation units (small effect size). The change in
      neuropsychological measures found in other antiepileptic medications (e.g., carbamazepine and
      topiramate) has been from 0.2 to 2.5 units (e.g., Meador et al., 2001).

      To obtain 20 completed subjects, experience from previous studies demonstrates a 50% dropout
      rate. Therefore, approximately 40 subjects will need to be enrolled to achieve the 20
      completed participants for this study.

      Analyses will be conducted on both intent-to-treat and per-protocol. Any subject who is
      valuable for the safety analysis that also has baseline and end of drug treatment period
      neuropsychological data available for each of the two drug periods will be evaluated for the
      intent-to-treat analyses of the parameters of interest. Mood and neuropsychological data will
      undergo analysis of variance (MANOVA) appropriate for a two-period crossover study.
      Alternative forms will be used when available. To compensate for practice effects and
      evaluate for measurement error, baseline will be defined as the average of the evaluations
      conducted at pre-treatment baseline and the post-treatment period (week 12).18 Subjects who
      discontinue prematurely will be tested two weeks after withdrawing. This will be considered
      the post-treatment period for these subjects.

      VIII. Risks and Benefit There is no benefit to participating in this study. In the pivotal
      trials 15 % receiving Levetiracetam discontinued the study compared to 11.6% receiving
      placebo. Levetiracetam has reported only non-serious, reversible side effects. The most
      common significant side effect of levetiracetam is somnolence (i.e., lethargy), asthenia,
      infection, dizziness, and unsteady gait. Less common side effects include thinking
      abnormalities, memory problems, anxiety, depression, agitation, vertigo, and paresthesias.
      Rarely, levetiracetam has been associated with psychotic disturbance that resolved after
      treatment was discontinued (0.7%). The adverse event profile of levetiracetam is generally
      less than that to other medications such as lamotrigine, topiramate, phenytoin,
      carbamazepine, and bactrim. All study medication should be discontinued at the first sign of
      hallucinations.

      VIII. Compensation. Subjects will be compensated for their time and inconvenience.
      Reimbursement assumes that a subject will invest about 14 hours over the three months of the
      study not including travel time. This is a significant imposition as we expect most
      volunteers to be gainfully employed. They will also be undergoing three blood draws and have
      the inconvenience of taking medications for almost two months. The compensation will be
      prorated to the amount of testing completed: $50 for screening visit, $200 for completing
      visit 3 (first treatment arm), $275 is given at visit 5 for completing the study. The maximal
      reimbursement is $525. Payment will be made at the end of participation in the study. Based
      on the subject volunteering 14 hours of their time, not including travel time, this equates
      to $37.50 per hour. This participation reimbursement rate is similar to the reimbursement
      rate of similar studies conducted at this institution and is also mirrored at other similar
      academic medical centers.

      IX. Volunteer Recruitment and Confidentiality. Advertisements in the form of flyers (Appendix
      3) will be distributed around University Hospital and Case Western Reserve University and in
      the hospital weekly flyer "Monday Morning". Volunteers face no harm to grades, job status,
      promotion or evaluation by participating or by withdrawing. Individuals within the Neurology
      Department will be excluded. Information will be confidential.

      X. REFERENCES

        1. Alsaadi, TM, Koopman, S, Apperson, M, Farias, S. Levetiracetam monotherapy for elderly
           patients with epilepsy. Seizure 2004;13(1):58-60.

        2. Baker GA , Jacoby A, Buck D, Stalgis, C, Monnet, D. Quality of Life of people with
           epilepsy: a European study. Epilepsia 1997; 38:353-362.

        3. Ben-Menachem E., & Gilland E. Efficacy and tolerability of levetiracetam during 1-year
           follow-up in patients with refractory epilepsy. Seizure 2003; 61:704-706.

        4. Bravo G, & Herbert R. Age- and education-specific reference values for the Mini-mental
           and Modified Mini-Mental State Examinations derived from a non-demented elderly
           population. Intr J Geriatric Psychiatry 1997;12:1008-1018.

        5. Cramer, JA, Leppik, IE, De Rue, K., Edrich, P., & Kraemer, G. Tolerability of
           levetiracetam in elderly patients with CNS disorders. Epilepsy Research 2003(a);
           56:135-145.

        6. Cramer JA., Katrie DR., Devinsky O., Edrich P., Trimble MR. A systematic review of the
           behavioral effects in levetiracetam in adults with epilepsy, cognitive disorders, or an
           anxiety disorder during clinical trials. Epilepsy Behav 2003(b); 4:124-132.French J.,
           Edrich P., Cramer JA. (A systematic review of the safety profile of levetiracetam: A new
           antiepileptic drug. Epilepsy Res 2001; 47; 77-90.

        7. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental
           State Exam by age and education level. Journal of the American Medical Association 1993,
           269: 2389.

        8. Ferrendelli J., French J., Leppik I., Morrell M., Herbeuval A., Han J., et al. Use of
           levetiracetam in a population of patients aged 65 years and older: A subset analysis of
           the KEEPERTM trial. Epilepsy Behav 2003;4:702-709.

        9. Hauser, W.A., and Hesdorffer, D.C. Epilepsy: Frequency, causes, and consequences.

           New York: Demos Publications, 1990; 1-51.

       10. Kraemer G., Edrich P. Levetiracetam in elderly patients with epilspsy [abstract].
           Epilepsia 2001;42(Suppl 7):142-3.

       11. Martin R., Vogtle L., Gilliam F., and Faught E. Health related quality of life in senior
           adults with epilepsy: what we know from randomized clinical trials and suggestions for
           future research. Epilepsy and Behavior 2003, 4:626-634.

       12. Meador, K.J., Loring, D.W., Moore E.E., Thompson, W.A., Nichols, M.E., Oberzan, R.E.,
           Durkin, M.W., Gallagher, B.B., and King D.W. Comparative cognitive effects of
           phenobarbital, phenytoin, and valproate in healthy adults. Neurology 1995; 45:1494-1499.

       13. Meador, KJ, Loring, DW, Ray, PG, Murro, AM, King, DW, Perrine, KR, Vazquez, BR, Kiobasa,
           T. Differential cognitive and behavioral effects of carbamazepine and lamotrigine.
           Neurology 2001;56: 1177-1182.

       14. Meador, KJ., Loring, DW., Werz, MA., Ray, PG., Schoenberg, MR., Ogrocki, P., &
           Kaul-Gupta, R. Perceived Preference for Lamotrigine or Topiramate: Correlation with
           self-report inventories and neuropsycholotgical testing. Poster presented at the 56th
           Annual Meeting of the American Academy of Neurology, San Francisco, CA, April 2004.

       15. Morrell M., Leppik I., French J., Ferrendelli J., Han J., Magnus L. The KEEPERTM trial:
           Levetiracetam adjunctive treatment of partial-onset seizures in an open-label
           community-based study [published corrigendum appears in Epilepsy Res 2003; 56:209-210.
           Epilepsy Res 2003;54:153-61.

       16. Perucca E and Johannessen SI. The ideal pharmacokinetic properties of an antiepileptic
           drug: how close does Levetiracetam come? Epileptic Disorders 2003, 5(suppl1):S17-S26.

       17. Pryor FM, Ramsay RE, Keppra monotherapy in the elderly and in primary generalized
           epilepsy. 2003;44 suppl 9:270.

       18. Ramsay et al. Evaluation of epilepsy in elderly subjects. Epilepsia 2004; 45 (Suppl 9):
           16-21.

       19. Ramsay, RE, Rowan, AJ, Pryor FM, Collins, JF. Treatment of seizures in the elderly:
           final analysis form DVA cooperative study #428. Epilepsia 2003;44 (suppl 9):170.

       20. Werz, MA, Lang, P, Rienzo, T. Levetiracetam therapy for epilepsy: use and tolerability
           in the elderly. Epilepsia 2003;44 (suppl 9:280) (2.307).
    

Intervention name(s): Levetiracetam (Keppra)
Intervention type(s): Drug
Intervention MeSH terms: Levetiracetam
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Elderly; Epilepsy; Cognition; Health Outcome