Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-25T04:41:09.953Z Has data issue: false hasContentIssue false
  • English
  • Français

Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease

Published online by Cambridge University Press:  21 December 2012

Paula T. Trzepacz ,
Jeffrey Cummings ,
Thomas Konechnik ,
Tammy D. Forrester ,
Curtis Chang ,
Ellen B. Dennehy ,
Brian A. Willis ,
Catherine Shuler ,
Linda B. Tabas  and
Constantine Lyketsos
Paula T. Trzepacz*
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Jeffrey Cummings
Affiliation:
Cleveland Clinic, Lou Ruvo Center, Las Vegas, Nevada, USA
Thomas Konechnik
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Tammy D. Forrester
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Curtis Chang
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Ellen B. Dennehy
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Brian A. Willis
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Catherine Shuler
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Linda B. Tabas
Affiliation:
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
Constantine Lyketsos
Affiliation:
Department of Psychiatry, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
*
Correspondence should be addressed to: Paula T. Trzepacz, MD, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Phone: +317-997-7148; Fax: +317-276-7100. Email: [email protected].
Get access

Abstract

Background: Mibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimer's disease (AD).

Methods: Outpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimer's Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored.

Results: Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group.

Conclusion: Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues.

This trial is registered on ClinicalTrials.gov; ID: NCT00843518.

Keywords

AMPAAlzheimer's diseasemibampatoragitationaggressionneuropsychiatric symptomsglutamateNeuropsychiatric Inventory
Type
Research Article
Information
International Psychogeriatrics , Volume 25 , Issue 5 , May 2013 , pp. 707 - 719
Copyright
Copyright © International Psychogeriatric Association 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aalten, P.et al. (2007). Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dementia and Geriatric Cognitive Disorders, 24, 457–463. doi:10.1159/000110738.CrossRefGoogle ScholarPubMed
Alexopoulos, G. S., Abrams, R. C., Young, R. C. and Shamoian, C. A. (1988). Cornell Scale for Depression in Dementia. Biological Psychiatry, 23, 271–284.CrossRefGoogle ScholarPubMed
Ballard, C., Corbett, A., Chitramohan, R. and Aarsland, D. (2009). Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions. Current Opinion in Psychiatry, 22, 532–540. doi:10.1097/YCO.0b013e32833111f9.CrossRefGoogle ScholarPubMed
Blanchard, B. J., Chen, A., Rozeboom, L. M., Stafford, K. A., Weigele, P. and Ingram, V. M. (2004). Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proceedings of the National Academy of Sciences USA, 101, 14326–14332. doi:10.1073/pnas.0405941101.CrossRefGoogle ScholarPubMed
Chappell, A. S., Gonzales, C., Williams, J., Witte, M. M., Mohs, R. C. and Sperling, R. (2007). AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Neurology, 68, 1008–1012. doi:10.1212/01.wnl.0000260240.46070.7c.CrossRefGoogle ScholarPubMed
Cohen-Mansfield, J., Werner, P., Watson, V. and Pasis, S. (1995). Agitation among elderly persons at adult day-care centers: the experiences of relatives and staff members. International Psychogeriatrics, 7, 447–458.CrossRefGoogle ScholarPubMed
Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A. and Gornbein, J. (1994). The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology, 44, 2308–2314.CrossRefGoogle ScholarPubMed
Davis, J. D. and Tremont, G. (2007). Impact of frontal systems behavioral functioning in dementia on caregiver burden. The Journal of Neuropsychiatry and Clinical Neurosciences, 19, 43–49. doi:10.1176/appi.neuropsych.19.1.43.CrossRefGoogle ScholarPubMed
Dennehy, E. B., Kahle-Wrobleski, K., Sarsour, K. and Milton, D. R. (2012). Derivation of a brief measure of agitation and aggression in Alzheimer's disease. International Journal of Geriatric Psychiatry. doi:10.1002/gps.3807.Google ScholarPubMed
Doody, R. S.et al. (2001). Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 56, 1154–1166.CrossRefGoogle ScholarPubMed
Folstein, M. F., Folstein, S. E. and McHugh, P. R. (1975). “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189–198.CrossRefGoogle ScholarPubMed
Fox, C.et al. (2012). Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo-controlled trial. PLoS One, 7: e35185 (Epub May 2). doi:10.1371%2Fjournal.pone.0035185.CrossRefGoogle ScholarPubMed
Galasko, D., Kershaw, P. R., Schneider, L., Zhu, Y. and Tariot, P. N. (2004). Galantamine maintains ability to perform activities of daily living in patients with Alzheimer's disease. Journal of American Geriatrics Society, 52, 1070–1076. doi:10.1111/j.1532-5415.2004.52303.x.CrossRefGoogle ScholarPubMed
Gates, M., Ogden, A. and Bleakman, D. (2001). Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro. Neuropharmacology, 40, 984–991. doi:10.1016/S0028-3908(01)00040-5.CrossRefGoogle ScholarPubMed
Gilley, D. W., Bienias, J. L., Wilson, R. S., Bennett, D. A., Beck, T. L. and Evans, D. A. (2004). Influence of behavioral symptoms on rates of institutionalization for persons with Alzheimer's disease. Psychological Medicine, 34, 1129–1135. doi:10.1017/S0033291703001831.CrossRefGoogle ScholarPubMed
Grace, J. and Malloy, P. F. (2001). Frontal Systems Behavior Scale (FrSBe): Professional Manual. Lutz, FL: Psychological Assessment Resources.Google Scholar
Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology, revised. Bethesda, MD: US Department of Health, Education, and Welfare.Google Scholar
Herrmann, N. and Lanctôt, K. L. (2007). Pharmacologic management of neuropsychiatric symptoms of Alzheimer's disease. Canadian Journal of Psychiatry, 52, 630–646.CrossRefGoogle Scholar
Herrmann, N., Lanctôt, K. L. and Khan, L. R. (2004). The role of norepinephrine in the behavioral and psychological symptoms of dementia. Journal of Neuropsychiatry and Clinical Neurosciences, 16, 261–276. doi:10.1176/appi.neuropsych.16.3.261.CrossRefGoogle ScholarPubMed
Hirono, N., Mega, M. S., Dinov, I. D., Mishkin, F. and Cummings, J. L. (2000). Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Archives of Neurology, 57, 861–866. doi:10-1001/pubs.Arch Neurol.-ISSN-0003-9942-57-6-noc90037.CrossRefGoogle ScholarPubMed
Holmes, C.et al. (2001). Psychosis and aggression in Alzheimer's disease: the effect of dopamine receptor gene variation. Journal of Neurology, Neurosurgery, and Psychiatry, 71, 777–779. doi:10.1136/jnnp.71.6.777.CrossRefGoogle ScholarPubMed
Jeste, D. V.et al. (2008). ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology, 33, 957–970. doi:10.1038/sj.npp.1301492.CrossRefGoogle ScholarPubMed
Jhee, S. S.et al. (2006). Multiple-dose plasma pharmacokinetic and safety study of LY450108 and LY451395 (AMPA receptor potentiators) and their concentration in cerebrospinal fluid in healthy human subjects. Journal of Clinical Pharmacology, 46, 424–432. doi:10.1177/0091270006286899.CrossRefGoogle ScholarPubMed
Lopez, O. L., Kaufer, D., Reiter, C. T., Carra, J., DeKosky, S. T. and Palmer, A. M. (1996). Relationship between CSF neurotransmitter metabolites and aggressive behavior in Alzheimer's disease. European Journal of Neurology, 3, 153–155.CrossRefGoogle Scholar
Lyketsos, C. G.et al. (2011). Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers & Dementia, 7, 532–539. doi:10.1016/j.jalz.2011.05.2410.CrossRefGoogle ScholarPubMed
Lynch, G. (2004). AMPA receptor modulators as cognitive enhancers. Current Opinion in Pharmacology, 4, 4–11. doi:10.1016/j.coph.2003.09.009.CrossRefGoogle ScholarPubMed
Mackowiak, M., O'Neill, M. J., Hicks, C. A., Bleakman, D. and Skolnick, P. (2002). An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study. Neuropharmacology, 43, 1–10. doi:10.1016/S0028-3908(02)00066-7.CrossRefGoogle ScholarPubMed
Madsen, U., Ebert, B. and Krogsgaard-Larsen, P. (1994). Modulation of AMPA receptor function in relation to glutamatergic abnormalities in Alzheimer's disease. Biomedicine & Pharmacotherapy, 48, 305–311.CrossRefGoogle ScholarPubMed
Malloy, P., Tremont, G., Grace, J. and Frakey, L. (2007). The Frontal Systems Behavior Scale discriminates frontotemporal dementia from Alzheimer's disease. Alzheimers & Dementia, 3, 200–203. doi:10.1016/j.jalz.2007.04.374.CrossRefGoogle ScholarPubMed
Murman, D. L., Chen, Q., Powell, M. C., Kuo, S. B., Bradley, C. J. and Colenda, C. C. (2002). The incremental direct costs associated with behavioral symptoms in AD. Neurology, 59, 1721–1729.CrossRefGoogle ScholarPubMed
O'Neill, M. J. (2004). SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer's and Parkinson's disease. Expert Opinion on Investigational Drugs, 13, 1369–1373. http://informahealthcare.com/doi/pdf/10.1517/13543784.13.10.1369.CrossRefGoogle ScholarPubMed
Reinikainen, K. J., Soininen, H. and Riekkinen, P. J. (1990). Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy. Journal of Neuroscience Research, 27, 576–586. doi:10.1002/jnr.490270419.CrossRefGoogle ScholarPubMed
Robinson, A., Spencer, B. and White, L. (2007). Understanding Difficult Behaviors: Practical Suggestions for Coping with Alzheimer's Disease and Related Illnesses. Eastern Michigan University Alzheimer's Education Program Ypsilanti, MI: Eastern Michigan University. Available at: http://www.amazon.com/Understanding-Difficult-Behaviors-suggestionsAlzheimers/dp/0978902009.Google Scholar
Rosen, W. G., Mohs, R. C. and Davis, K. L. (1984). A new rating scale for Alzheimer's disease. American Journal of Psychiatry, 141, 1356–1364.Google ScholarPubMed
Rosenheck, R. A.et al. (2007). Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer's disease. Archives of General Psychiatry, 64, 1259–1268. doi:10.1001/archpsyc.64.11.1259.CrossRefGoogle Scholar
Shin, I. S., Carter, M., Masterman, D., Fairbanks, L. and Cummings, J. L. (2005). Neuropsychiatric symptoms and quality of life in Alzheimer's disease. American Journal of Geriatric Psychiatry, 13, 469–474. doi:10.1176/appi.ajgp.13.6.469.CrossRefGoogle Scholar
Sperling, R. A., Jack, C. R. Jr. and Aisen, P. S. (2011). Testing the right target and right drug at the right stage. Science Translational Medicine, 3, 1–5. doi:10.1126/scitranslmed.3002609.CrossRefGoogle ScholarPubMed
Sukonick, D. L.et al. (2001). The 5-HTTPR*S/*L polymorphism and aggressive behavior in Alzheimer's disease. Archives of Neurology, 58, 1425–1428. doi:10-1001/pubs.Arch Neurol.-ISSN-0003-9942-58-9-noc00319.CrossRefGoogle Scholar
Sultzer, D. L.et al. (2008). Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. American Journal of Psychiatry, 165, 844–854. doi:10.1176/appi.ajp.2008.07111779.CrossRefGoogle ScholarPubMed
Sweet, R. A.et al. (2001). The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer's disease. International Psychogeriatrics, 13, 401–409. doi:10.1017/S1041610201007827.CrossRefGoogle Scholar
Tekin, S. (2001). Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer's disease. Annals of Neurology, 49, 355–361. doi:10.1002/ana.72.CrossRefGoogle Scholar
Trinh, N. H., Hoblyn, J., Mohanty, S. and Yaffe, K. (2003). Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. Journal of the American Medical Association, 289, 210–216. doi:10.1001/jama.289.2.210.CrossRefGoogle ScholarPubMed
Trzepacz, P. T., Mittal, D., Torres, R., Kanary, K., Norton, J. and Jimerson, N. (2001). Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. The Journal of Neuropsychiatry and Clinical Neurosciences, 13, 229–242. doi:10.1176/appi.neuropsych.13.2.229.CrossRefGoogle ScholarPubMed
Vandergriff, J., Huff, K., Bond, A. and Lodge, D. (2001). Potentiation of responses to AMPA on central neurones by LY392098 and LY404187 in vivo. Neuropharmacology, 40, 1003–1009. doi:10.1016/S0028-3908(01)00031-4.CrossRefGoogle ScholarPubMed
Walton, H. S. and Dodd, P. R. (2007). Glutamate-glutamine cycling in Alzheimer's disease. Neurochemistry International, 50, 1052–1066. doi:10.1016/j. neuint.2006.10.007.CrossRefGoogle ScholarPubMed
Weiner, M. F.et al. (2000). Quantifying behavioral disturbance in Alzheimer's disease patients. Journal of Psychiatric Research, 34, 163–167. doi:10.1016/S0022-3956(99)00042-4.CrossRefGoogle ScholarPubMed
Wilcock, G. K., Ballard, C. G., Cooper, J. A. and Loft, H. (2008). Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer's disease: a pooled analysis of 3 studies. Journal of Clinical Pharmacology, 69, 341–348.Google ScholarPubMed
Wood, S.et al. (2000). The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. American Journal of Geriatric Psychiatry, 8, 75–83.CrossRefGoogle ScholarPubMed
Woodward, M., Jacova, C., Black, S. E., Kertesz, A., Mackenzie, I. R., Feldman, H. and the ACCORD investigator group (2010). Differentiating the frontal variant of Alzheimer's disease. International Journal of Geriatric Psychiatry, 25, 732–738. doi:10.1002/gps.2415.CrossRefGoogle ScholarPubMed
Wu, X.et al. (2004). AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3-kinase-dependent activation in extracellular signal-regulated kinase to upregulate BDNF gene expression. Journal of Neurochemistry, 90, 807–818. doi:10.1111/j.1471-4159.2004.02526.x.CrossRefGoogle ScholarPubMed
Yamada, K. A. (2000). Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease. Expert Opinion on Investigational Drugs, 9, 765–778. doi:10.1517/13543784.9.4.765.CrossRefGoogle ScholarPubMed
Zhao, P., Ignacio, S., Beattie, E. C. and Abood, M. E. (2008). Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity. European Journal of Neuroscience, 27, 572–579. doi:10.1111/j.1460-9568.2008.06041.x.CrossRefGoogle ScholarPubMed