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Executive Summary

THA FAILS TO SHOW "SIGNIFICANT" BENEFIT IN MID-STAGE ALZHEIMER's PATIENTS after eight weeks of treatment with the acetylcholinesterase inhibitor in combination with lecithin. The results of the 52-patient study in intermediate-stage Alzheimer's disease were published in the May 3 New England Journal of Medicine. The investigators, Serge Gauthier, MD, et al. concluded that the results of the study of 100 mg/day oral tetrahydroaminoacridine (THA)/lecithin combination "fail to demonstrate a significant clinical benefit of THA given orally." The efficacy of the THA/lecithin treatment was measured via five standardized scales of memory and mental status, ability to function, and behavior -- the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rate Scale-II, and the behavioral scale of Reisberg et al. Patient safety during the double-blind, crossover, multicenter studies was determined via close clinical and caregiver monitoring and by measurements of liver enzyme levels taken at least twice a week, according to the report. The researchers found that "the only statistically significant improvement [during the double-blind phase of the study]...occurred in the MMS score after four weeks of treatment with oral THA in a mean does of 85 mg per day. No significant change occurred during the other weeks of treatment." The patients, as reported by their caregivers, showed "an increase in spontaneity of speech and functional activities (such as setting a table or answering the telephone) during the titration period and a diminution in these features during the washout period," the investigators said. Spontaneity "was not regained" during the second double-blind phase. These results, the researchers contend, suggest either that the patients adapted to THA's potential clinical effects, that THA's benefit is not carried on after an abrupt or prolonged washout period, or that "the apparent clinical benefit was not related to THA but to the expectations of the families early in the study." The studies, conducted at the McGill University Centre for Studies in Aging (Montreal), add to the conflicting reports on THA efficacy and point out the difficulties of showing empirical improvements in Alzheimer's patients from short-term studies on small populations. The researchers acknowledged that higher doses of THA "might achieve clinically observable results that would be statistically significant according to cognitive, functional and behavioral scales." Warner-Lambert, which plans to file an NDA in June for its THA product Cognex, has indicated that studies conducted by the company are showing positive results. Warner-Lambert is testing the drug at a 40-80 mg a day dosage regimen in over 200 patients in the U.S. The Cognex NDA will also include supplemental data Warner-Lambert recently acquired from a three-month, double-blind, placebo-controlled crossover trial conducted by U.K.-based Shire Pharmaceutical. According to an editorial in the April 28 British Medical Journal, a preliminary analysis of the 13-week Shire study "suggests that there is clear evidence" of THA's efficacy. The McGill researchers did not use an "enriched" patient population for their studies -- "i.e., patients who had a predetermined increase in the score on a given scale during dose titration" -- while Warner-Lambert's studies focus on such patients. The McGill researchers said they avoided an enriched patient sample because they wanted results that could be generalized to the overall Alzheimer's patient population. The McGill study consisted of a 10-week dose-titration period followed by a crossover period using the largest tolerated dose of THA, which was from 50-100 mg/day. Titration was followed by a four-week washout period with an abrupt withdrawal of THA treatment, an eight-week period of treatment with THA or placebo, and a second identical four-week washout period, followed by a second eight-week period with THA or placebo treatment. The THA dose was gradually increased over the eight-week treatment periods, to a maximum of 100 mg/day, given in three doses during the day with meals. Of the 52 patients starting the studies reported in the New England Journal, six could not complete the titration-washout period and seven could not complete the 20-week, doubleblind period for a variety of reasons. Of the 39 completing the double-blind phase, nine patients taking THA had some problems with drug toxicity: their liver enzyme levels were "three or more times the upper limit of normal," according to Gauthier and his group. However, the researchers note, "within one to six weeks after THA was stopped, the levels returned to normal." The researchers had halted an initial double-blind, crossover efficacy and safety study of the THA/lecithin combo during the titration phase because of dose-related liver toxicity in 80% of the patients. That study was using doses up to 200 mg daily.

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