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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; 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; 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; 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. doi:10.1001/jama.1992.03490180055026.
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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)


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