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Clinical Trials in Dementia

  • Encarnita Raya-Ampil (a1) and Jeffrey L. Cummings (a2)



Dementia, particularly Alzheimer's disease (AD), is increasing by patient population included in clinical trials. The methodology for trials of AD patients have been defined in terms of outcomes, standard measures and analytic techniques. Trial methodology is evolving with experience as new potential therapies become available. Screening criteria, instrumentation choices, duration of trials and analytic strategies may have a profound impact on the conclusions that can be derived from trials. The components of AD trials are reviewed in detail in this chapter.


Corresponding author

Correspondence should be addressed to: Jeffrey L. Cummings, MD, Departments of Neurology and Psychiatry and Biobehavioral Sciences, Reed Neurological Research Center, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Suite 2-238, P.O. Box No. 951769, Los Angeles, CA 90095-1769, USA; Tel: 310 206 5239; Fax: 310 206 5287; Email:


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A Randomized Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Galantamine in Subjects with Mild Cognitive Impairment (MCI) Clinically at Risk for Development of Clinically Probably Alzheimer's Disease. Gal-INT-18 and Gal-INT-11. Accessed on November 17, 2005.
AD2000 Collaborative Group (2004). Long term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial. Lancet, 353, 21052115.
Aisen, P., Davis, K., Berg, J., et al. (2000). A randomized controlled trial of prednisone in Alzheimer's disease. Neurology, 54, 588593.
Aisen, P., Schafer, K., Grundman, M., et al. (2003). Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression. Journal of the American Medical Association, 289, 28192826.
Alexopoulos, G., Abrams, R., Young, R., et al. (1988). Cornell Scale for depression in dementia. Biological Psychiatry, 23, 271284.
Alzheimer Association (2004). Research consent for cognitively impaired adults: recommendations for institutional review boards and investigators. Alzheimer Disease & Associated Disorders, 18, 171175.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington, DC: American Psychiatric Association, 143147.
Begg, C., Cho, M., Eastwood, S., et al. (1996). Improving the quality of reporting of randomized controlled trials: the CONSORT statement. Journal of the American Medical Association, 276, 637639.
Blacker, D., Albert, M., Bassett, S., et al. (1994). Reliability and validity of NINCDS–ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative. Archives of Neurology, 51, 11981204.
Brodaty, H., Ames, D., Snowdon, J., et al. (2003). A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation and psychosis of dementia. Journal of Clinical Psychiatry, 64, 134143.
Burke, W., Miller, O., Rubin, E., et al. (1988). Reliability of the Washington University Clinical Dementia Rating. Archives of Neurology, 45, 3132.
Cohen-Mansfield, J. (1985). Agitated behaviors in the elderly ill. Preliminary results in the cognitively deteriorated. Journal of the American Geriatrics Society, 34, 722727.
Corey-Bloom, J., Anand, R., Veach, J., et al. (1998). A randomized trial evaluating the efficacy and safety of ENA 73 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. International Journal of Geriatric Psychopharmacology, 1, 5565.
Cummings, J. (2003). Use of acetylcholinesterase inhibitors in clinical practice: evidence-based recommendations. American Journal of Geriatric Psychiatry, 11, 131145.
Cummings, J., Mega, M., Gray, K., et al. (1994). The neuropsyciatric inventory: an efficient tool for comprehensively assessing psychopathology in dementia. Neurology, 44, 23082314.
Cummings, J., Cyrus, P., Bieber, F., et al. (1998). Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Neurology, 50, 12141221.
Davis, K., Thal, L., Gamzu, E., et al. (1992). A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. New England Journal of Medicine, 327, 12531259.
Davis, K., Marin, D., Kane, R., et al. (1997). The Caregiver Activity Survey (CAS): development and validation of a new measure for caregivers of persons with Alzheimer's disease. International Journal of Geriatric Psychiatry, 12, 978988.
De Deyn, P., Rabheru, K., Rasmussen, A., et al. (1999). A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology, 53, 946955.
DeJong, R., Osterlund, O., Roy, G. (1989). Measurement of quality-of-life changes in patients with Alzheimer's disease. Clinical Therapeutics, 11, 545554.
Doody, R., Stevens, J., Beck, C., 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, 11541166.
Doraiswamy, P., Kaiser, L., Bieber, F., et al. (2001). The Alzheimer's Disease Assessment Scale: evaluation of psychometric properties and patterns of cognitive decline in multicenter clinical trials of mild-to-moderate Alzheimer's disease. Alzheimer Disease & Associated Disorders, 15, 174183.
Ernst, R.L. & Hay, J.W. (1994). The US economic and social costs of AD revisited. American Journal of Public Health, 84, 12611264.
Evans, D.A. (1990). Estimated prevalence of Alzheimer's disease in the United States. Milbank Q 68, 267289.
Evans, D.A., Funkenstein, H.H., Albert, M.S., et al. (1989). Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. Journal of the American Medical Association, 26, 25512556.
Everitt, B. Pickler, A. (2004). Statistical Aspects of the Design and Analysis of Clinical Trials. London: Imperial College Press, pp. 4550, 203–204.
Farlow, M., Gracon, S., Hershey, L., et al. (1992). A controlled trial of tacrine in Alzheimer's disease. Journal of the American Medical Association, 268, 25232529.
Feldman, H., Gauthier, S., Hecker, J., et al. (2001). A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology, 57, 613620.
Ferris, S., Lucca, U., Mohs, R., et al. (1997). Objective psychometric tests in clinical trials of dementia drugs. Alzheimer Disease & Associated Disorders, 11, 3438.
Folstein, M., Folstein, S., McHugh, P. (1975). Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189198.
Galasko, D., Bennett, D., Sano, M., et al. (1997). An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Disease & Associated Disorders, 11 (Suppl. 2), S33S39.
Gauthier, S., Bodick, N., Erzigkeit, E., et al. (1997). Activities of daily living as an outcome measure in clinical trials of dementia drugs. Alzheimer Disease & Associated Disorders, 11 (Suppl. 3), 67.
Gelinas, I., Gauthier, L., McIntyre, M., et al. (1999). Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Americal Journal of Occupational Therapy, 53, 471481.
Guy, W. (ed.) (1976). Clinical Global Impression (CGI). ECDEU assessment manual for psychopharmacology. Rockville, MD: US Department of Health and Human Services, Public Health Service, Alcohol Drug Abuse and Mental Health Administration. NIMH Psychopharmacology Research Branch. pp. 218222.
Holmes, C., Clairns, N., Lantos, P., et al. (1999). Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies. British Journal of Psychiatry, 174, 4550.
Hughes, C., Berg, L., Denziger, W., et al. (1982). A new clinical scale for the staging of dementia. British Journal of Psychiatry, 140, 566572.
Institute on Aging (1996). Progress Report on Alzheimer's Disease 1996. Bethesda, Md: National Institute on Aging, NIH publication, pp. 964137.
Katz, I., Jeste, D., Mintzer, J., et al. (1999). Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Journal of Clinical Psychiatry, 60, 107115.
Kay, S., Opler, L., Lindenmayer, J., et al. (1989). The positive and negative syndrome scale: a rationale and standardization. British Journal of Psychiatry, 155 (Suppl. 7), 5965.
Knapp, M., Knopman, D., Solomon, P., et al. (1994). A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. Journal of the American Medical Association, 271, 985991.
Knopman, D., Knapp, M., Bracon, S., et al. (1994). The clinician interview-based impression (CIBI): a clinician's global change rating scale in Alzheimer's disease. Neurology, 44, 23152321.
Koepsell, T. Weiss, N. (2003). Epidemiologic Methods. New York: Oxford University Press, pp. 6467, 261, 327329.
Lawton, M. Brody, E. (1969). Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist, 9, 179186.
Le Bars, P., Katz, M., Berman, N., et al. (1997). A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo Biloba for dementia. Journal of the American Medical Association, 278, 13271332.
Leber, P. (1990). Guidelines for the Clinical Evaluation of Antidementia Drugs, Food and Drug Administration, Washington, D.C.
Leber, P. (1997). Observations and suggestions on antidementia drug development. Alzheimer Disease & Associated Disorders, 10, S1, 3135.
Lopez, O.L., Litvan, I., Catt, K.E., et al. (1999). Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology, 53, 12921299.
Lyketsos, C., Sheppard, J., Steele, C., et al. (2000). Randomized, placebo-controlled, double-blind clinical trial of sertraline in the treatment of depression complicating Alzheimer's disease: initial results from the depression in Alzheimer's disease study. American Journal of Psychiatry, 157, 16861689.
McKhann, G., Drachman, D., Folstein, M., et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology, 34, 939944.
Moher, D., Schulz, K., Altman, D., et al. (2001). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Journal of the American Medical Association, 285, 19871991.
Mohs, R., Doody, R., Morris, J., et al. (2001). A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology, 57, 481488.
Morris, J., Edland, S., Clark, C., et al. (1993). The consortium to establish a registry for Alzheimer's disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease. Neurology, 43, 24572465.
Morris, J., Cyrus, P., Orazem, J., et al. (1998). Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. Neurology, 50, 12221230.
Morris, J.C., Storandt, M., Miller, P., et al. (2001). Mild cognitive impairment represents early-stage Alzheimer's disease. Archives of Neurology, 58, 397405.
Mulnard, R., Cotman, C., Kawas, C., et al. (2000). Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. Journal of the American Medical Association, 283, 10071015.
National Institute of Health, National Institute on Aging (1999). Progress Report on Alzheimer's Disease 1999 (NIH Pub. No. 99-4664). Bethesda, MD: US Department of Health and Human Services.
O'Connor, D.W., Pollitt, P., Hyde, J.B., et al. (1989). The reliability and validity of the mini-mental state in a British community survey. Journal of Psychiatric Research 23, 8796.
Overall, J. Gorham, D. (1962). The Brief Psychiatric Rating Scale. Psychological Reports, 10, 799812.
Overall, J. Gorhal, D. (1988). Introduction: the Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacology Bulletin, 24, 9799.
Patterson, M. Bolger, J. (1994). Assessment of behavioral symptoms in Alzheimer's disease. Alzheimer Disease & Associated Disorders, 8 (Suppl. 3), 420.
Petersen, R.C., Doody, R., Kurz, A., et al. (2001). Current concepts in mild cognitive impairment. Archives of Neurology, 58, 19851992.
Petersen, R.C., Thomas, R.G., Grundman, M., et al. (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine, 352, 23792388.
Porteinsson, A., Tariot, P., Erb, R., et al. (2001). Placebo-controlled study of divalproex sodium for agitation in dementia. American Journal of Geriatric Psychiatry 9, 5866.
Raskind, M., Peskind, E., Wessel, T., et al. (2000). Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology, 54, 22612268.
Reines, S., Block, G., Morris, J., et al. (2004). Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology, 62, 6671.
Reisberg, B., Ferris, S., de Leon, M., et al. (1982). The Global Deterioration Scale for assessment of primary degenerative dementia. American Journal of Psychiatry, 138, 11361139.
Reisberg, B., Scaln, S., Franssen, E., et al. (1994). Dementia staging in chronic care populations. Alzheimer Disease & Associated Disorders, 8 (Suppl. 1), S188S205.
Reisberg, B., Auer, S.R., Monteiro, I.M., et al. (1996). Behavioral pathology in Alzheimer's disease (BEHAVE-AD) rating scale. International Psychogeriatrics, 8 (Suppl. 3), 301308.
Reisberg, B., Doody, R., Stoffler, A., et al. (2003). Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Medicine, 348, 13331341.
Rockwood, K., Mintzer, J., Truyen, L., et al. (2001). Effects of a flexible galantamine dose in Alzheimer's disease: a randomized, controlled trial. Journal of Neurology Neurosurgery and Psychiatry, 71, 589595.
Rogers, S., Doody, R., Mohs, R., et al. (1998a). Donepezil improves cognition and global function in Alzheimer's disease. Archives of Internal Medicine, 158, 10211031.
Rogers, S., Farlow, M., Doody, R., et al. (1998b). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology, 50, 136145.
Rosen, W., Mohs, R., Davis, K., et al. (1984). A new rating scale for Alzheimer's disease. American Journal of Psychiatry, 141, 13561364.
Rosler, M., Anand, R., Cicin-Sain, A., et al. (1999). Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomized controlled trial. British Medical Journal, 318, 633638.
Salloway, S., Ferris, S., Kluger, A., et al. (2004). Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology, 63, 651657.
Sano, M., Ernesto, C., Klauber, M., et al. (1996). Rationale and design of a multicenter study of selegiline and A-tocopherol in the treatment of Alzheimer disease using novel clinical outcomes. Alzheimer Disease & Associated Disorders, 10, 132140.
Sano, M., Ernesto, C., Thomas, R., et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. New England Journal of Medicine, 336, 12161222.
Scharf, S., Mander, A., Ugoni, A., et al. (1999). A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology, 53, 197201.
Schneider, L., Olin, J., Doody, R., et al. (1997). Validity and reliability of the Alzheimer's disease cooperative study-Clinical Global Impression of change. Alzheimer Disease & Associated Disorders, 11 (Suppl. 2), S22S32.
Schneider, L., Tariot, P., Lyketsos, C., et al. (2001). National Institute of Mental Health Clinical Antipsychotic Trial of Inervention Effectiveness (CATIE): Alzheimer disease trial methodology. American Journal of Geriatric Psychiatry, 9, 346390.
Schoenmaker, N. & Van Gool, W. (2004). The age gap between patients in clinical studies and in the general population: a pitfall for dementia research. Lancet Neurology, 3, 627630.
Tariot, P., Erb, R., Podgorski, C., et al. (1988). Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. American Journal of Psychiatry, 155, 5461.
Tariot, P., Mack, J., Patterson, M., et al. and the CERAD Behavioral Pathology Committee (1995). The CERAD Behavior Rating Scale for Dementia (BRSD). American Journal of Psychiatry, 152, 13491357.
Tariot, P., Solomon, P., Morris, J., et al. (2000). A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology, 54, 22692276.
Thal, L., Carta, A., Clarke, W., et al. (1996). A 1-year multicenter placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer's disease. Neurology, 47, 705711.
Tierney, M., Fisher, R., Anthony, J., et al. (1988). The NINCDS–ADRDA Work Group criteria for the clinical diagnosis of probable Alzheimer's disease: a clinicopathologic study of 57 cases. Neurology, 38, 359364.
Weiner, M., Koss, E., Wild, K., et al. (1996). Measures of psychiatric symptoms in Alzheimer patients: a review. Alzheimer Disease & Associated Disorders, 10, 2030.
Whitehouse, P. (1997). Pharmacoeconomics of dementia. Alzheimer Disease & Associated Disorders, 11 (Suppl. 5), S22S33.
Wimo, A., Wetterholm, A., Mastey, Y., et al. (1998). Evaluation of the healthcare resource utilization and caregiver time in anti-dementia drug trials. In: Wimo, A., Jonsson, B., Karlson, G., Wilblad, B. (eds.), Health Economics of Dementia. Chichester, England: John Wiley, 465499.
Winblad, B., Wimo, A. Almkvist, O. (2000). Outcome measures in Alzheimer's disease: Do they go far enough? Dementia and Geriatric Cognitive Disorders, 11 (Suppl. 1), 310.
Winblad, B., Engedal, K., Soininen, H., et al. (2001). A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology, 57, 489495.
World Health Organization (1993). The ICD-10 Classification of Mental and Behavioral Disorders. Diagnostic Criteria for Research. Geneva, Switzerland: World Health Organization.
Zhong, K., Tariot, P., Minkwitz, M.C., et al. (2004). Quetiapine for the treatment of agitation in the elderly institutionalized patients with dementia: a randomized, double blind trial. International Conference on Alzheimer's Disease and Related Disorders meeting, Poster # P2-442.

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Clinical Trials in Dementia

  • Encarnita Raya-Ampil (a1) and Jeffrey L. Cummings (a2)


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