Ignite Creation Date:
2024-05-05 @ 12:02 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00221988
Status:
COMPLETED
Last Update Posted:
2022-05-18
First Post:
2005-09-16
Brief Title:
Effects of Keppra on Thinking Emotions and Balance in Elderly Healthy Volunteers
Sponsor:
University Hospitals Cleveland Medical Center
Organization:
University Hospitals Cleveland Medical Center
Study Overview
Official Title:
A Randomized Double-Blind Cross-over Study of the Cognitive and Mood Effects of KEPPRA Levetiracetam Tablets in Healthy Older Adults
Status:
COMPLETED
Status Verified Date:
2022-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 thinkingbalance 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 61000 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 20036 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 to85 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 al2003 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 11 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 patients current health status The study physician will review PCP medical records to assure participants meet the study inclusionexclusion 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 investigators opinion compliant able to follow the investigators instructions and visit the clinic on schedule cooperative and reliable
4 Subjects must score within -10 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 1Visit 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 -10 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 1000mgday 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 eg 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 01 to 06 units A minimum power of 080 A minimum detectable difference in neuropsychological tests scores was set at a 05 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 005 the minimum N needed is 18 subjects With 20 participants assuming a within subject standard deviation of 05 units the minimum detectable difference will be 0467 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 02 SD units With a smaller within subject SD and using the same parameters above N 20 yields a minimum detectable difference of 0187 standard deviation units small effect size The change in neuropsychological measures found in other antiepileptic medications eg carbamazepine and topiramate has been from 02 to 25 units eg 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 1218 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 116 receiving placebo Levetiracetam has reported only non-serious reversible side effects The most common significant side effect of levetiracetam is somnolence ie 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 07 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 3750 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 200413158-60
2 Baker GA Jacoby A Buck D Stalgis C Monnet D Quality of Life of people with epilepsy a European study Epilepsia 1997 38353-362
3 Ben-Menachem E Gilland E Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy Seizure 2003 61704-706
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 1997121008-1018
5 Cramer JA Leppik IE De Rue K Edrich P Kraemer G Tolerability of levetiracetam in elderly patients with CNS disorders Epilepsy Research 2003a 56135-145
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 2003b 4124-132French 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 20034702-709
9 Hauser WA and Hesdorffer DC 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 200142Suppl 7142-3
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 4626-634
12 Meador KJ Loring DW Moore EE Thompson WA Nichols ME Oberzan RE Durkin MW Gallagher BB and King DW Comparative cognitive effects of phenobarbital phenytoin and valproate in healthy adults Neurology 1995 451494-1499
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 200156 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 56209-210 Epilepsy Res 200354153-61
16 Perucca E and Johannessen SI The ideal pharmacokinetic properties of an antiepileptic drug how close does Levetiracetam come Epileptic Disorders 2003 5suppl1S17-S26
17 Pryor FM Ramsay RE Keppra monotherapy in the elderly and in primary generalized epilepsy 200344 suppl 9270
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 200344 suppl 9170
20 Werz MA Lang P Rienzo T Levetiracetam therapy for epilepsy use and tolerability in the elderly Epilepsia 200344 suppl 9280 2307
Background Antiepileptic Drugs And Cognitive Dysfunction Epilepsy is the most common debilitating neurologic disorder with a prevalence of about 61000 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 20036 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 to85 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 al2003 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 11 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 patients current health status The study physician will review PCP medical records to assure participants meet the study inclusionexclusion 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 investigators opinion compliant able to follow the investigators instructions and visit the clinic on schedule cooperative and reliable
4 Subjects must score within -10 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 1Visit 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 -10 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 1000mgday 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 eg 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 01 to 06 units A minimum power of 080 A minimum detectable difference in neuropsychological tests scores was set at a 05 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 005 the minimum N needed is 18 subjects With 20 participants assuming a within subject standard deviation of 05 units the minimum detectable difference will be 0467 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 02 SD units With a smaller within subject SD and using the same parameters above N 20 yields a minimum detectable difference of 0187 standard deviation units small effect size The change in neuropsychological measures found in other antiepileptic medications eg carbamazepine and topiramate has been from 02 to 25 units eg 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 1218 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 116 receiving placebo Levetiracetam has reported only non-serious reversible side effects The most common significant side effect of levetiracetam is somnolence ie 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 07 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 3750 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 200413158-60
2 Baker GA Jacoby A Buck D Stalgis C Monnet D Quality of Life of people with epilepsy a European study Epilepsia 1997 38353-362
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Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| UHC 06-04-52 | None | None | None |