Does Memantine Improve Verbal Memory Task Performance in Subjects With Partial Epilepsy and Memory Dysfunction? - Full Text View

Purpose

Many patients with epilepsy have memory deficits in the setting of otherwise normal intelligence. Unfortunately, the treatment options for memory dysfunction in patients with epilepsy are limited. The investigators are conducting a study to evaluate the effects of memantine for the treatment of verbal memory dysfunction in subjects with localization-related seizures. The study involves randomization to memantine therapy or placebo, with cognitive testing and EEG pre- and post-treatment, as well as after an open-label memantine treatment phase.

The primary aim of this study is to evaluate the efficacy of memantine for the treatment of verbal memory dysfunction in subjects with left temporal lobe epilepsy. The investigators expect that verbal memory task performance will improve in those taking memantine, but not in those taking a placebo.

The investigators propose that the expected benefit of memantine is specific to verbal memory in subjects with left temporal lobe seizures, rather than representing an overall improvement in cognitive function. The investigators expect no improvement on other cognitive tasks in either the memantine or placebo groups.

The investigators will evaluate whether subjects with left temporal lobe epilepsy and memory difficulties have self-reported improvement in memory while taking memantine. The investigators expect improvement of self-rated memory function on the Quality of Life in Epilepsy Patient Inventory (QOLIE-89) in the memantine group, but no change on this scale in the placebo group.

Condition	Intervention
Epilepsy	Drug: Memantine Other: Sugar Pill


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Does Memantine Improve Verbal Memory Task Performance in Subjects With Localization-related Epilepsy and Memory Dysfunction? A Randomized, Double-Blind, Placebo-Controlled Trial

Resource links provided by NLM:

Genetics Home Reference related topics: autosomal dominant partial epilepsy with auditory features pyridoxal 5'-phosphate-dependent epilepsy

MedlinePlus related topics: Epilepsy Memory

Drug Information available for: Memantine Memantine hydrochloride

U.S. FDA Resources

Further study details as provided by American Academy of Neurology:

Primary Outcome Measures:

The change scores from pre- and post-treatment neuropsychological test evaluations will be compared between the placebo and memantine treatment groups. If the distributions are normal, we will perform a two-sample t-test. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To test the hypothesis that improvement will be selective for verbal memory, change scores on the non-verbal tasks will be compared between the placebo and memantine treatment groups. If the distributions are normal, we will conduct a two-sample t-test. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To test the hypothesis that treatment with memantine will result in subjective improvement of memory function, the change scores from the QOLIE-89 will be evaluated. If the distributions are normal, we will proceed with a two-sample t-test [ Time Frame: 2 years ] [ Designated as safety issue: No ]
A secondary analysis will examine the possible sustained benefit of continued memantine use. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
The prediction is that subjects taking placebo will demonstrate improvement in the SRT-CLTR and 7-24 Spatial Memory Test scores between the second (post-placebo) and third (post-memantine) testing sessions. The expectation is that subjects randomized to memantine will demonstrate no change in memory test scores between the second (post-memantine) and third (post-memantine) testing sessions, reflecting sustained improvement from baseline. If the distributions are normal, we will conduct paired t-tests. If the distributions appear non-normal, we will use Wilcoxon signed rank tests.


Estimated Enrollment:	96
Study Start Date:	January 2009
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Memantine Subjects will randomly assigned to take either a placebo or memantine for 13 weeks. The assignment will be double-blind, neither the study members nor the subject will know if he/she is taking memantine or a placebo.	Drug: Memantine All subjects in the treatment group will be placed on memantine. The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the first phase of the study. At the conclusion of the first 13 weeks, subjects will discontinue the treatment (memantine or placebo) and enter the open label phase. Other Name: Namenda Drug: Memantine Open label: When the blinded phase is complete (Weeks 1-13), all subjects will receive open-label treatment with memantine (Weeks 14-26). The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the study. At the conclusion of the study, subjects will discontinue the treatment. Other Name: Namenda
Placebo Comparator: Sugar Pill Subjects will be randomly assigned to take either memantine or a placebo. The study is double-blind, and neither the study members nor the subject will know if he/she is taking memantine or a placebo.	Other: Sugar Pill In the control arm of the study, subjects will take one placebo sugar pill per day for one week, then increase to one tablet twice per day for the following 12 weeks. At the end of this phase of the study, subjects will enter the open-label phase (unblinded treatment with memantine). Other Name: Placebo

Arms

Assigned Interventions

Experimental: Memantine

Subjects will randomly assigned to take either a placebo or memantine for 13 weeks. The assignment will be double-blind, neither the study members nor the subject will know if he/she is taking memantine or a placebo.

Drug: Memantine

All subjects in the treatment group will be placed on memantine. The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the first phase of the study. At the conclusion of the first 13 weeks, subjects will discontinue the treatment (memantine or placebo) and enter the open label phase.

Other Name: Namenda

Drug: Memantine

Open label: When the blinded phase is complete (Weeks 1-13), all subjects will receive open-label treatment with memantine (Weeks 14-26). The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the study. At the conclusion of the study, subjects will discontinue the treatment.

Other Name: Namenda

Placebo Comparator: Sugar Pill

Subjects will be randomly assigned to take either memantine or a placebo. The study is double-blind, and neither the study members nor the subject will know if he/she is taking memantine or a placebo.

Other: Sugar Pill

In the control arm of the study, subjects will take one placebo sugar pill per day for one week, then increase to one tablet twice per day for the following 12 weeks. At the end of this phase of the study, subjects will enter the open-label phase (unblinded treatment with memantine).

Other Name: Placebo

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years to 65 Years (Adult)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

18-65 years of age
Normal IQ as estimated by the Wechsler Test of Adult Reading (WTAR)
Able to give consent
Able to live independently and complete activities of daily living
Stable frequency of seizures. There is no minimum/maximum criteria for the frequency of partial seizures. Those with infrequent secondary generalized seizures may participate, with infrequent seizures defined as two or fewer per year.
The subject's treating physician does not believe a change in anticonvulsant regimen to be warranted. The anticonvulsant drugs must remain unchanged during the 26 week trial.
Partial-onset seizures. Seizure type will be determined by clinical history, MRI, SPECT and/or PET imaging, and interictal and/or ictal EEG.
Either symptomatic or idiopathic seizures.

Exclusion Criteria:

Non-epileptic seizures
Prior surgical resection for treatment of seizures
Progressive neurologic illness (i.e. tumor evident on MRI)
Current alcohol or drug abuse, as this may affect memory by other mechanisms. This information may be obtained by self-report, from the referring physician or by medical record.
Diagnosis of Alzheimer's disease, nutritional deficiency, infection or metabolic/electrolyte disorder causing memory loss.
Non-native English speaking and/or multilingual.
Seizure(s) must not have occurred within 3 days of testing.
Subjects who are pregnant will not be eligible to take part in the study, as memantine is classified as a Pregnancy Category B drug and may pose risk to the fetus.
Women who are breastfeeding may not participate in this study.
Those with renal tubular acidosis or infections of the urinary tract will not be eligible for participation, as memantine is renally cleared and conditions that alkalinize the urine may reduce clearance of the drug.
Subjects with severe renal impairment, defined as a creatinine clearance of ≤29 mL/min, will be excluded as such patients may not tolerate the proposed dosing schedule.

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: NCT01054599

Contacts


Contact: Beth A Leeman, M.D.	404-778-3181	baleeman@partners.org
Contact: Samantha R Donovan, B.S.	617-643-4617	sdonovan@mclean.harvard.edu

Locations


United States, Georgia
Emory University	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Beth A Leeman, MD 404-778-3181 baleeman@partners.org
Principal Investigator: Beth A Leeman, MD
United States, Massachusetts
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Principal Investigator: Lauren Moo, M.D.
Sub-Investigator: Beth A Leeman, M.D.
Newton-Wellesley Hospital	Recruiting
Newton, Massachusetts, United States, 02462
Contact: Eduardo Garcia, MD 617-928-1500 eduardo.garciamd@gmail.com
Principal Investigator: Eduardo Garcia, MD

Sponsors and Collaborators

American Academy of Neurology

Forest Laboratories

Investigators


Principal Investigator:	Lauren Moo, M.D.	Massachusetts General Hospital

More Information

Additional Information:

For related information This link exits the ClinicalTrials.gov site

Publications:

Blum D. Decline in Verbal Memory Associated with Duration of Epilepsy: An Intracarotid Amobarbital Study. Epilepsy Behav. 2001 Oct;2(5):448-453.

Busch RM, Frazier TW, Haggerty KA, Kubu CS. Utility of the Boston naming test in predicting ultimate side of surgery in patients with medically intractable temporal lobe epilepsy. Epilepsia. 2005 Nov;46(11):1773-9.

Diaz-Asper CM, Dopkins S, Potolicchio SJ Jr, Caputy A. Spatial memory following temporal lobe resection. J Clin Exp Neuropsychol. 2006 Nov;28(8):1462-81.

Dodrill CB, Ojemann GA. Do recent seizures and recent changes in antiepileptic drugs impact performances on neuropsychological tests in subtle ways that might easily be missed? Epilepsia. 2007 Oct;48(10):1833-41. Epub 2007 May 23.

Fisher RS, Bortz JJ, Blum DE, Duncan B, Burke H. A pilot study of donepezil for memory problems in epilepsy. Epilepsy Behav. 2001 Aug;2(4):330-4.

Halsband U. Bilingual and multilingual language processing. J Physiol Paris. 2006 Jun;99(4-6):355-69. Epub 2006 May 24. Review.

Hamberger MJ, Palmese CA, Scarmeas N, Weintraub D, Choi H, Hirsch LJ. A randomized, double-blind, placebo-controlled trial of donepezil to improve memory in epilepsy. Epilepsia. 2007 Jul;48(7):1283-91. Epub 2007 May 1.

Helmstaedter C, Elger CE, Lendt M. Postictal courses of cognitive deficits in focal epilepsies. Epilepsia. 1994 Sep-Oct;35(5):1073-8.

Hermann BP, Seidenberg M, Schoenfeld J, Peterson J, Leveroni C, Wyler AR. Empirical techniques for determining the reliability, magnitude, and pattern of neuropsychological change after epilepsy surgery. Epilepsia. 1996 Oct;37(10):942-50.

Kelsey JE, Sanderson KL, Frye CA. Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801. Behav Brain Res. 2000 Jan;107(1-2):59-69.

Kim KH, Relkin NR, Lee KM, Hirsch J. Distinct cortical areas associated with native and second languages. Nature. 1997 Jul 10;388(6638):171-4.

Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, Gates J, Penovich P, Al-Asmi A, Dubeau F, Jones-Gotman M. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia. 2003 Mar;44(3):339-47.

Lucas TH 2nd, McKhann GM 2nd, Ojemann GA. Functional separation of languages in the bilingual brain: a comparison of electrical stimulation language mapping in 25 bilingual patients and 117 monolingual control patients. J Neurosurg. 2004 Sep;101(3):449-57.

Lutz MT, Helmstaedter C. EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy. Epilepsy Behav. 2005 Dec;7(4):708-14. Epub 2005 Nov 2.

McLean MJ, Gupta RC, Dettbarn WD, Wamil AW. Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat. Toxicol Appl Pharmacol. 1992 Jan;112(1):95-103.

Meador KJ, Loring DW, Vahle VJ, Ray PG, Werz MA, Fessler AJ, Ogrocki P, Schoenberg MR, Miller JM, Kustra RP. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology. 2005 Jun 28;64(12):2108-14.

Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003 Apr 3;348(14):1333-41.

Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006 Jan;63(1):49-54.

Sabsevitz DS, Swanson SJ, Morris GL, Mueller WM, Seidenberg M. Memory outcome after left anterior temporal lobectomy in patients with expected and reversed Wada memory asymmetry scores. Epilepsia. 2001 Nov;42(11):1408-15.

Schefft BK, Testa SM, Dulay MF, Privitera MD, Yeh HS. Preoperative assessment of confrontation naming ability and interictal paraphasia production in unilateral temporal lobe epilepsy. Epilepsy Behav. 2003 Apr;4(2):161-8.

Stroup E, Langfitt J, Berg M, McDermott M, Pilcher W, Como P. Predicting verbal memory decline following anterior temporal lobectomy (ATL). Neurology. 2003 Apr 22;60(8):1266-73.

Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317-24.

Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse. 1989;3(2):154-71. Review.

Zipf-Williams EM, Shear PK, Strongin D, Winegarden BJ, Morrell MJ. Qualitative block design performance in epilepsy patients. Arch Clin Neuropsychol. 2000 Feb;15(2):149-57.


Responsible Party:	Beth Leeman, M.D., Assistant in Neuroscience, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT01054599 History of Changes
Other Study ID Numbers:	2008P000107
Study First Received:	December 1, 2009
Last Updated:	January 4, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by American Academy of Neurology:


epilepsy memory memantine localization related epilepsy focal epilepsy

Additional relevant MeSH terms:


Epilepsy Epilepsies, Partial Brain Diseases Central Nervous System Diseases Nervous System Diseases Memantine Antiparkinson Agents	Anti-Dyskinesia Agents Dopamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents

ClinicalTrials.gov processed this record on September 26, 2016