P3-457

S510

Poster P3:: Tuesday Posters

pected of having ongoing bacterial infection with Borrelia, long term antibiotic therapy (6 months) will be instituted along with 200 hrs of DC EMF therapy. A parallel trial of Alzheimer patients diagnosed with Lyme by ILADS criteria with 6 months of Doxycycline/ Tindazole without DC electromagnetic therapy is also planned.

P3-455

DONEPEZIL TREATMENT FOR ALZHEIMER’S DISEASE IN CHRONIC DIALYSIS PATIENTS

Konstantina G. Yiannopoulou, Athina K. Euthymiou, Kleanthis D. Karydakis, General Hospital of Athens, Athens, Greece. Contact e-mail: [email protected] Background: Donepezil is one of the cholinesterase inhibitors that are indicated for the treatment of mild to moderate Alzheimer’s Disease. Pharmacokinetic analysis has shown that donepezil is primarily eliminated by renal excretion rather than biliary excretion in humans. Therefore, patients with impaired renal function are at high risk for toxicity caused by accumulation of this drug. It is also well known that dialysis patients have very often cholinergic disorders. On the other hand, with the increasing number of long-term chronic dialysis patients, the prevalence of cognitive disorders is increasing in the elderly of them. Because of the above mentioned special risks, prescription of acetylocholinesterase inhibitors, such as donepezil, to be avoided is prescribed. There is only one study that evaluates the pharmacokinetics of donepezil in patients with impaired renal function and only one case-report with donepezil treatment in a chronic-dialysis patient. Objectives: This pilot study aimed to investigate whether there is a safe dose of donepezil to be administered in chronic dialysis patients with Alzheimer’s disease and if this treatment offers a possible benefit to them. Methods: We studied three cases of chronic hemodialysis outpatients (2 men and 1 woman, 72, 86 and 65 years old respectively), that were diagnosed as having moderate Alzheimer’s disease. Study subjects underwent a baseline clinical and laboratory assessment and a neuropsychological examination (including MMSE, GDS, NPI and IADL scale), that it was repeated every month. All patients were followed for 6 months. We began treatment with donepezil on the lower dose of 2.5mg/day orally and we enhanced the dose to 5mg/day one month later. Results: After 1 month’s treatment, they improved to a controllable psychiatric condition, without having any adverse effects. After 3 months of treatment with the higher dose, their cognitive and executive functions were slightly improved and their behavior was remarkably improved, without experiencing any episodes of drug toxicity. The patients’ condition remained stable for 6 months after the initial administration of the drug. Conclusion: Our cases indicate that donepezil treatment under prudent use may be well tolerated and have a beneficial impact on chronic hemodialysis patients with Alzheimer’s disease.

P3-456

DIFFERENTIAL QUANTITATIVE EEG EFFECTS OF RIVASTIGMINE AND MEMANTINE IN ALZHEIMER PATIENTS

Georg Adler1, Oliver Hennig1, Eva Grips1, Petra van Keulen2, Martin Roser2, Ferenc Tracik3, Lutz Froelich1, 1Central Institute of Mental Health, Mannheim, Germany; 2Psychiatrisches Zentrum Calw, Calw, Germany; 3Novartis GmbH, Nu¨rnberg, Germany. Contact e-mail: [email protected] Background: In the quantitative EEG of Alzheimer patients, mean theta power is increased and left temporal alpha coherence is decreased. Under treatment with the acetylcholine esterase inhibitor rivastigmine theta power decreases. Theta power decrease in Alzheimer patients within one or two weeks of rivastigmine treatment has been found to be related to therapeutic response, a strong theta decrease predicting a good therapeutic efficacy of rivastigmine. Little is known about the quantitative EEG effects of memantine, a noncompetitive NMDA receptor antagonist, which is also used for the treatment of Alzheimer’s disease. Objective(s): We conduct an ongoing study comparing the short-term EEG effects of rivastigmine and memantine in Alzheimer patients. Methods: An interim analysis was performed, using the data of 49 Alzheimer patients (NINCDS-ADRDA criteria), 15 men and 34 women at ages of 62 to 85 years (mean: 76 years). EEG was assessed prior to treatment initiation. Then, the patients were randomized in a 1:1 ratio to either treatment with rivastigmine (3 mg p.d.) or memantine (10 mg p.d.). After 2 weeks of treatment, a second EEG recording was performed. EEG data were quantitatively analyzed, calculating mean theta power and left temporal alpha coherence before and under treatment with either rivastigmine or memantine. Results: Mean theta power decreased under both treatments. However, theta decrease was only found significant under rivastigmine (from 34.4 ⫹ 23.4 ␮V2 to 20.1 ⫹ 14.7 ␮V2; df⫽23, t⫽3.908, p⫽0.001), not under memantine (from 30.1 ⫹ 30.6 ␮V2 to 26.6 ⫹ 24.9 ␮V2; df⫽24, t⫽1.388, p⫽0.178). Theta decrease was significantly stronger under rivastigmine than under memantine treatment (-14.3 ⫹ 17.8 ␮V2 vs. -3.6 ⫹ 12.8 ␮V2; df⫽47, t⫽-2.403, p⫽0.021). Left temporal alpha coherence remained unchanged under either treatment. Conclusions: Rivastigmine showed significant EEG effects, probably brought about by its cholinergic efficacy. We failed to demonstrate such effects in memantine, although they might be anticipated by vigilanceincreasing properties of this substance. P3-457

TREATMENT OF SEVERE ALZHEIMER’S DISEASE WITH DONEPEZIL: RESULTS FROM A 24-WEEK, PARALLEL, PLACEBO-CONTROLLED STUDY IN JAPAN

Akira Homma1, Itaru Arimoto2, Kasumi Daidoji2, Toshio Ohbayashi2, Hideo Ozawa3, 1Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Eisai Co., Ltd., Tokyo, Japan. Contact e-mail: [email protected] Background: Post-hoc analyses of donepezil treatment in more severe AD patients have demonstrated benefits in cognitive and functional measures. These results require substantiation in prospective, controlled trials with populations clinically defined as having severe AD. Objective(s): To determine donepezil’s efficacy and tolerability in severe Alzheimer’s disease (AD). Methods: Severe AD patients (MMSE scores, 1-12; MHI scores, 6; FAST scores 6) were enrolled in this parallel, double-blind, placebo-controlled study in 66 sites in Japan. Patients (n⫽325) were randomized to donepezil 5-mg (after 3mg/d for 2 weeks, n⫽110), donepezil 10-mg (after 3mg/d for 2 weeks followed by 5-mg/d for 4 weeks, n⫽103), or placebo (n⫽112) for 24 weeks. Twenty three patients withdrew from the study before administering study drugs. A total of 290 patients (n⫽96 in 5-mg, n⫽92 in 10-mg, 102 in placebo, respectively) were analyzed for efficacy. Statistical analyses were done on full analysis set last observation carried forward (FAS-LOCF) population and FAS observed case (FAS-OC) at Week 24 population. Primary outcome measures were change from baseline to endpoint (FAS-LOCF) in Severe Impairment

Poster P3:: Tuesday Posters Battery (SIB) total score and Clinician’s Interview Based Impression of Change-Plus (CIBIC-Plus) scores at endpoint (FAS-LOCF). They were assessed using ANCOVA for SIB and CMH test for CIBIC-plus. CIBICPlus was also analyzed using collapsed categories (1-3⫽improved; 4⫽no change; 5-7⫽worsened). Results: Donepezil 5-mg and 10-mg were significantly superior to placebo in SIB for FAS-LOCF (mean differences of 6.7 and 9.0 respectively from placebo, p ⬍ 0.001) and for FAS-OC (p ⬍ 0.001). Both CIBIC-Plus analyses showed statistically significant differences in favor of donepezil 10-mg over placebo for FAS-LOCF and FAS-OC (p⫽0.003, p⫽0.005, respectively). Collapsed analysis for CIBICPlus was similar to as follows; for FAS-LOCF (p⫽0.001) and for FAS-OC (p⫽0.001). Most AEs (94%) were mild or moderate. AEs reported more than 5% and twice of placebo were vomiting, elevated CK level, diarrhea, anorexia, fever, abrasion, constipation, loss of appetite and restlessness. Conclusions: The results of this study confirmed the superiority of donepezil 10-mg/d to placebo in severe AD patients on SIB and CIBIC-Plus. The administrations of 5-mg and 10-mg of donepezil for severe AD are safe and well tolerated. P3-458

EFFECTIVITY OF TREATMENT OF MILD COGNITIVE IMPAIRED SUBJECTS USING RIVASTIGMINE: FUNCTIONAL MRI

Arun Bokde1, Patricia Lopez-Bayo1, Thomas Meindl2, Christine Born2, Susanne Pechler1, Frank Faltraco1, Stefan J. Teipel1, H.-J. Moeller1, Harald Hampel1, 1Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany; 2Institute for Clinical Radiology, Ludwig-Maximilian University, Munich, Germany. Contact e-mail: [email protected] Background: Mild cognitive impairment (MCI) is a transition period between normal cognitive function and Alzheimer’s disease (AD). In MCI subjects cholinergic changes occur in the brain leading to cognitive dysfunction. The low levels of acetylcholine can be restored using pharmacological agents such as rivastigmine. Functional MRI (fMRI) is a useful tool to detect neurochemical changes and monitor effects of treatment. Objective(s): To measure the reactivity of the brain to treatment with rivastigmine in MCI subjects. Methods: There were 8 MCI patients enrolled into a randomized study design. The first 3 months were doubleblind (verum or placebo) followed by 9 months open label verum. Functional imaging was performed at entry, after 3 months, and after 6 months into entry. The MCI subjects received 2 Rivastigmine doses per day of 1.5 mg (first month), 3.0 mg (second month) and 4.5 (from third month to end of study). CERAD neuropsychological score was performed at entry, 3 months, 6, months and 12 months after entry. Brain function was tested using a face and location matching task. Results: There were 6 MCI patients who received Rivastgmine in the double blind stage (2 received placebo). The CERAD scores of the MCI subjects remained stable over the 1 year period. In the placebo arm, there was no change in activation compared to entry (after 3 months placebo). After 3 months of rivastigmine, there was a decrease in activation in medial frontal areas and increase in temporal lobe areas compared to baseline activation during the face matching task. In the location matching task there was decreased activation in the parietal lobe and increased activation in hippocampus compared to baseline activation. After 6 months of treatment with rivastigmine, there were no changes in brain activation in either the face or location matching task compared to baseline. Conclusions: Rivastigmine treatment maintained cognitive function, as determined using the CERAD scores. The changes in brain function after 3 months show that MCI subjects relied less on higher order cognitive systems to perform the task. This study has shown that measurements of brain function changes due to cholinergic treatment are possible.

P3-459

S511 DOUBLE-BLIND PLACEBO-CONTROLLED EVALUATION OF THE SAFETY AND EFFICACY OF PHENSERINE TARTRATE (PT) FOR THE TREATMENT OF MILD TO MODERATE ALZHEIMER’S DISEASE (AD)

Gosse Bruinsma1, Bengt Winblad2, Ezio Giacobini3, Lutz Froelich4, Edward J. Walters5, Lawrence Friedhoff6, 1Axonyx Inc., New York, NY, USA; 2Karolinska Institute, Huddinge, Sweden; 3H.U.G., Geneva, Switzerland; 4Heidelberg University, Mannheim, Germany; 5Edon LLC, Allentown, NJ, USA; 6Pharmaceutical Special Projects Group LLC, River Vale, NJ, USA. Contact e-mail: [email protected] Objective: Evaluation of the safety and efficacy of phenserine tartrate as treatment for mild to moderate Alzheimer’s disease. Methods: Originally, 900 patients were to be enrolled in two separate and identical 26-week trials at 72 sites in 12 countries comparing placebo, 10-mg twice daily (BID) and 15-mg BID phenserine tartrate, but these were curtailed to 12 weeks and 255 patients and the databases were combined for this analysis. Active-treated patients were started at 5-mg BID and titrated in 5-mg bid increments over 4-week periods. The protocol-defined primary analysis was the 12-week last observation carried forward (LOCF). However, many patients had evaluations after 12 weeks. Results: Adverse events consisted primarily of GI and CNS effects, as expected. [Mean ⫾ SD (N)]. ADAS-cog Change from Baseline

CIBICⴙ

Dose

12 WeeksLOCF

Weeks 12-26

26 Weeks

12WeeksLOCF

Weeks 1226

26 Weeks

Placebo

-1.9 ⫾ 5.84 (81) -1.3 ⫾ 6.30 (83) -2.5 ⫾ 6.21 (83)

-0.66 ⫾ 5.44 (63) -1.31 ⫾ 6.04 (57) -3.18ⴞ 9.50ⴱ (52)

-2.9 ⫾ 5.70 (12) -3.5 ⫾ 4.82 (15) -4.8 ⫾ 8.99 (11)

3.72 ⫾ 1.12 (81) 3.89 ⫾ 0.77 (82) 3.80 ⫾ 1.03 (83)

3.95 ⫾ 1.25 (66) 4.02 ⫾ 1.03 (62) 3.59ⴞ1.16† (54)

4.36 ⫾ 1.12 (11) 3.73 ⫾ 0.8 (15) 3.55 ⫾ 1.44 (11)

10-mg bid 15-mg bid

ⴱp⫽0.0286 relative to placebo †p⫽ 0.0568 relative to placebo.

The 15-mg group was numerically superior to placebo, becoming statistically significant for the ADAS-cog at 12-26 weeks. One could speculate that the increase of treatment effect over time could be due to delayed onset or an effect on disease progression. This speculation is consistent with MRI measurements of brain volumes in a small number of patients in a separate double-blind study. Conclusion: This study suggests that phenserine may be an effective, well tolerated treatment for mild to moderate AD. A definitive trial is justified. P3-460

SAFETY, TOLERABILITY AND PHARMACOKINETICS OF MULTIPLE DOSES OF LECOZOTAN IN PATIENTS WITH ALZHEIMER’S DISEASE

Ronald S. Black1, Ermellina Murray1, Sangeeta Raje1, Yonggang Zhao1, Prisca Lucas1, Kerri Wilks2, Beth Safirstein2, Denis Crimmins3, Michael Woodward4, 1Wyeth Research, Collegeville, PA, USA; 2MD Clinical, Hallandale Beach, FL, USA; 3Central Coast Neurosciences Research, East Gosford, Australia; 4Aged and Residential Care Services, Austin Health, Heidelberg, Australia. Contact e-mail: [email protected] Background: Lecozotan is a 5-HT1A antagonist being developed for the symptomatic treatment of cognitive deficits associated with Alzheimer’s disease (AD). The cognitive efficacy of lecozotan has been demonstrated in multiple animal models relevant to AD. Objective(s): The objective of this study was to assess the safety, tolerability, and pharmacokinetic parameters of multiple ascending fixed oral doses of immediate-release (IR) and sustained-release (SR) lecozotan in patients with mild to moderate AD. Methods: This was a randomized, double-blind, placebo-controlled, multiple ascending dose study in 56 patients (pts). Four dosing cohorts received lecozotan IR or placebo twice daily for 28 days at a ratio of 3:1 (active:placebo). Total daily doses of lecozotan in these cohorts were 1 mg (8 pts total in cohort), 2 mg (8 pts), 5 mg (8 pts) and 10 mg (16 pts). An