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Article
November 11, 1992

A Controlled Trial of Tacrine in Alzheimer's Disease

Author Affiliations

From the Center for Alzheimer's Disease and Related Disorders, Indiana University Medical Center, Indianapolis (Dr Farlow); the Clinical Reseach Department (Dr Gracon and Ms Dolan-Ureno) and Biostatistics Department (Ms Lewis), Parke-Davis/Warner-Lambert Company, Ann Arbor, Mich; Department of Neurology, Veterans Affairs Medical Center, State University of New York at Buffalo (Dr Hershey); and West Palm Beach Neurological Group, West Palm Beach, Fla (Dr Sadowsky).
Neurological Associates, Boise, Idaho; Southwest Institute of Clinical Research, Rancho Mirage, Calif; Sunnybrook Medical Center, University of Toronto (Ontario); Department of Neurology, The Graduate Hospital, University of Pennsylvania, Philadelphia; Department of Neurology, University of Missouri Health Sciences Center, Columbia; Deborah Marshall, Nancy Westergaard, Center for Behavioral Medicine, Wheat Ridge, Colo; Center for Alzheimer's Disease and Related Disorders, Indiana University Medical Center, Indianapolis; Department of Behavioral Neurology, Henry Ford Hospital, Detroit, Mich; Department of Neurology, University of Virginia Health Sciences Center, Charlottesville; Department of Neurology, Veterans Affairs Medical Center, State University of New York at Buffalo; Department of Neurology, Medical College of Ohio, Toledo; Psyehopharmacology Research Association of Princeton (NJ); Institute of Mental Health Research, University of Ottawa (Ontario); Department of Medicine, Neurology Division, Roger Williams General Hospital, Providence, RI; Pacific Medical Research Services, Redwood City, Calif; West Palm Beach (Fla) Neurological Group; Department of Psychiatry and Neurology, Tulane University School of Medicine, New Orleans, La; Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, Richmond; Brooklyn (NY) Veterans Affairs Medical Center; Department of Psychiatry, Health Sciences Center, State University of New York at Stony Brook; Neurological Associates, Palos Heights, Ill; Pacific Research Network, Chula Vista, Calif; Department of Neurology, University of Michigan Medical Center, Ann Arbor; Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Mich.

JAMA. 1992;268(18):2523-2529. doi:10.1001/jama.1992.03490180055026
Abstract

Objective.  —To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease.

Design.  —A 12-week, double-blind, placebo-controlled, parallel-group study.

Setting.  —Outpatients at 23 centers.

Patients.  —Men and women with probable Alzheimer's disease, at least 50 years old, mildly to moderately impaired, without other significant medical conditions.

Interventions.  —In the initial 6 weeks, patients received placebo, 20 mg/d of tacrine, or 40 mg/d of tacrine. In the second 6 weeks, half received the same treatment and half increased tacrine dose: those receiving placebo increased to 20 mg/d, those receiving 20 mg/d increased to 40 mg/d, and those receiving 40 mg/d increased to 80 mg/d.

Primary Outcome Measures.  —Alzheimer's Disease Assessment Scale (ADAS) cognitive component and clinician-rated Clinical Global Impression of Change (CGIC).

Results.  —Four hundred sixty-eight patients entered. After 12 weeks, dose-related improvement was significant on the ADAS cognitive (P=.014), clinician-rated CGIC (P=.014), and caregiver-rated CGIC (P=.006). Comparison of 80 mg/d with placebo showed significant improvement on the ADAS cognitive (P=.015), clinician-rated CGIC (P=.016), and caregiver-rated CGIC (P=.028). Significant effects appeared as early as 6 weeks on the ADAS cognitive and caregiver-rated CGIC. Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment. Reversible asymptomatic transaminase elevations greater than three times normal occurred in 25% of patients. Other treatment-related events included nausea and/or vomiting (8%), diarrhea (5%), abdominal pain (4%), dyspepsia (3%), and rash (3%).

Conclusions.  —These results confirm the efficacy and safety of tacrine in some patients with Alzheimer's disease. After 12 weeks, the magnitude of the treatment effect is clinically important and recognized by the physician and caregiver. Liver toxicity is reversible and easily detected by weekly alanine aminotransferase determinations.(JAMA. 1992;268:2523-2529)

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