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A Controlled Trial of Tacrine in Alzheimer's Disease
Martin Farlow, MD;
Stephen I. Gracon, DVM;
Linda A. Hershey, MD;
Karen W. Lewis, MS;
Carl H. Sadowsky, MD;
Jann Dolan-Ureno, BSN;
the Tacrine Study Group;
Stephen W. Asher, MD;
Craig Beaver, PhD;
Diane Hamilton;
Scott M. Bergman, MD;
Linda F. Roger, RN;
Sandra E. Black, MD;
Sandra Carr, RN;
Tamara Winchester;
Elizabeth Layne;
Christopher Clark, MD;
James Dexter, MD;
Eugene A. DuBoff, MD;
Martin Farlow, MD;
Hugh Hendrie, MB, ChB;
Judy Caress, RN;
Rhonna Shatz, DO;
George R. Hanna, MD;
H. Robert Brashear, MD;
Paula Damgaard, RN;
Linda A. Hershey, PhD, MD;
Kerry Donnelly, PhD;
Karen Burch, RN;
Richard W. Homan, MD;
A. John McSweeney, PhD;
Mary Ann Barczak, BSN;
Jeffrey A. Mattes, MD;
Allison M. Hermann, MA;
Erich Mohr, PhD;
Tilak Mendis, MD;
Jeremy Roberts, MB;
Linda Begin;
Margaret Sampson;
Brian R. Ott, MD;
Margaret C. Lannon, RN, MS;
J. Joseph Prendergast, MD;
Sherna Madan, MD;
Roxann Hanning, PAC;
Carl H. Sadowsky, MD;
Walter Martinez, MD;
Reed Stone, MD;
Paul Winner, MD;
Jose Zuniga, MD;
Laszlo J. Mate;
B. J. Ehlert, PhD;
Caria Lessard, RN;
Benjamin Seltzer, MD;
John R. Taylor, MD;
V. P. Calabrese, MD;
S. W. Harkins, PhD;
S. J. Weis;
Walter Slade, MD;
Barbara R. Sommer, MD;
Melvin Wichter, MD;
Michael Schwartz, MD;
Joey Eastman, RN;
Stephen G. Thein, Jr, PhD;
Geri Williams, LVN;
Judith A. Dewar, RN;
Norman L. Foster, MD;
Laurie A. Bluemlein, MS, RN;
Douglas J. Gelb, MD, PhD;
Stanley Berent, PhD;
Bruno Giordani, PhD;
Beth A. Baron, MS;
Sharie Myers, MS
JAMA. 1992;268(18):2523-2529.
Abstract
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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)
Author Affiliations
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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.
Footnotes
Dr Gracon and Mss Lewis and Dolan-Ureno are employees of the Warner-Lambert Company and own stock and hold options to purchase further stock in the company. Drs Farlow, Hershey, and Sadowsky own no stock or options in the Warner-Lambert Company.
A complete list of the participants in the Tacrine Study Group appears at the end of this article.
Reprint requests to Indiana University School of Medicine, Emerson Hall, Room 125, 545 Barnhill Dr, Indianapolis, IN 46202-5124 (Dr Farlow).
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