A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease

Kenneth L. Davis, Leon J. Thal, Elkan R. Gamzu, Charles S. Davis, Robert F. Woolson, Stephen I. Gracon, David A. Drachman, Lon S. Schneider, Peter J. Whitehouse, Toni M. Hoover, John C. Morris, Claudia H. Kawas, David S Knopman, Nancy L. Earl, Vinod Kumar, Rachelle S. Doody

Research output: Contribution to journalArticle

610 Citations (Scopus)

Abstract

Background. In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. Methods. Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. Results. At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P<0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. Conclusions. In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

Original languageEnglish (US)
Pages (from-to)1253-1259
Number of pages7
JournalNew England Journal of Medicine
Volume327
Issue number18
StatePublished - Oct 29 1992
Externally publishedYes

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Tacrine
Multicenter Studies
Alzheimer Disease
Placebos
Cholinesterase Inhibitors
Activities of Daily Living
Cognition
Cholinergic Neurons
Transaminases
Headache
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Davis, K. L., Thal, L. J., Gamzu, E. R., Davis, C. S., Woolson, R. F., Gracon, S. I., ... Doody, R. S. (1992). A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. New England Journal of Medicine, 327(18), 1253-1259.

A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. / Davis, Kenneth L.; Thal, Leon J.; Gamzu, Elkan R.; Davis, Charles S.; Woolson, Robert F.; Gracon, Stephen I.; Drachman, David A.; Schneider, Lon S.; Whitehouse, Peter J.; Hoover, Toni M.; Morris, John C.; Kawas, Claudia H.; Knopman, David S; Earl, Nancy L.; Kumar, Vinod; Doody, Rachelle S.

In: New England Journal of Medicine, Vol. 327, No. 18, 29.10.1992, p. 1253-1259.

Research output: Contribution to journalArticle

Davis, KL, Thal, LJ, Gamzu, ER, Davis, CS, Woolson, RF, Gracon, SI, Drachman, DA, Schneider, LS, Whitehouse, PJ, Hoover, TM, Morris, JC, Kawas, CH, Knopman, DS, Earl, NL, Kumar, V & Doody, RS 1992, 'A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease', New England Journal of Medicine, vol. 327, no. 18, pp. 1253-1259.
Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. New England Journal of Medicine. 1992 Oct 29;327(18):1253-1259.
Davis, Kenneth L. ; Thal, Leon J. ; Gamzu, Elkan R. ; Davis, Charles S. ; Woolson, Robert F. ; Gracon, Stephen I. ; Drachman, David A. ; Schneider, Lon S. ; Whitehouse, Peter J. ; Hoover, Toni M. ; Morris, John C. ; Kawas, Claudia H. ; Knopman, David S ; Earl, Nancy L. ; Kumar, Vinod ; Doody, Rachelle S. / A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. In: New England Journal of Medicine. 1992 ; Vol. 327, No. 18. pp. 1253-1259.
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abstract = "Background. In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. Methods. Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. Results. At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P<0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. Conclusions. In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.",
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T1 - A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease

AU - Davis, Kenneth L.

AU - Thal, Leon J.

AU - Gamzu, Elkan R.

AU - Davis, Charles S.

AU - Woolson, Robert F.

AU - Gracon, Stephen I.

AU - Drachman, David A.

AU - Schneider, Lon S.

AU - Whitehouse, Peter J.

AU - Hoover, Toni M.

AU - Morris, John C.

AU - Kawas, Claudia H.

AU - Knopman, David S

AU - Earl, Nancy L.

AU - Kumar, Vinod

AU - Doody, Rachelle S.

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N2 - Background. In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. Methods. Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. Results. At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P<0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. Conclusions. In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

AB - Background. In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. Methods. Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. Results. At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P<0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. Conclusions. In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

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