Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00221988 |
| Other study ID # |
UCB MRS001 |
| Secondary ID |
UHC 06-04-52 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 2004 |
| Est. completion date |
October 2007 |
Study information
| Verified date |
May 2022 |
| Source |
University Hospitals Cleveland Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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
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