T772
P4-339
Poster Presentations P4:
MRI EVIDENCE FOR A DISEASE-MODIFYING EFFECT OF GINKGO BILOBA EXTRACT IN A DEMENTIA PREVENTION TRIAL
Jeffrey A. Kaye, Hiroko Dodge, Tracy Zitzelberger, Milar Moore, Barry Oken, Oregon Health & Science University, Portland, OR, USA. Contact e-mail:
[email protected] Background: Decreased rates of brain volume loss are proposed as measures of “disease modifying” effects in dementia clinical trials. For dementia prevention studies, this method may be particularly important for demonstrating effects on the brain when asymptomatic. In this context we assessed whether Ginkgo Biloba extract (GBE) had an affect on rate of brain volume loss in normal elderly aged 85 and older followed in a randomized controlled trial (RCT) of dementia prevention. Methods: As part of a randomized, placebocontrolled, double-blind, 42-month study with 118 cognitively intact subjects (CDR ⫽ 0) randomized to standardized GBE or placebo each subject was scanned at baseline and then during annual follow-up exams using the same 1.5 T MRI equipment. Standard volumetric MRI image analysis procedures were used to assess the volumes of total brain, ventricular volume, white matter high signal (WMH) and hippocampus. Univariate analysis compared the yearly rates of volume change between the GBE and placebo groups. A mixed effects model of the changes in each brain volume over time was used to compare differences between the two groups, adjusting for the specific baseline brain volumes, baseline intracranial volume, sex, apoE genotype, and medication adherence. Results: There was a significantly (p ⫽ 0.02) lower rate of total brain volume loss in the GBE group (-0.9 ⫾ 1.1%/year) vs. the placebo group (-1.5 ⫾ 1.2%/year). The mixed model showed a significantly faster total brain loss among the placebo group (p ⫽ 0.02), compared with the GBE group. There was no significant difference between the GBE and placebo treated groups in the rate of change in ventricular, WMHS or hippocampal volumes. Conclusions: GBE treatment reduced the rate of brain lost in healthy seniors. This supports the clinical efficacy data adjusted for medication adherence, shown in our previous study (Neurology, 70(9), 2008). These results suggest a “disease-modifying” effect in a RCT prevention study. Larger prevention trials with greater statistical power to observe these effects are needed to confirm these observations. P4-340
CHOLINESTERASE INHIBITORS TOLERABILITY STUDY IN DEMENTIA WITH LEWY BODIES AND ALZHEIMER’S DISEASE
Radoslaw Magierski, Tomasz Sobow, Iwona Kloszewska, Medical University of Lodz, Lodz, Poland. Contact e-mail:
[email protected] Background: Few randomized controlled trials of the efficacy of cholinesterase inhibitors in dementia with Lewy bodies (DLB) have been published. The comparative tolerability of donepezil and rivastigmine in a
naturalistic sample of patients diagnosed as having mild to moderate Alzheimer’s disease (AD) and DLB has not been properly studied to date. The aim of this study was to compare the tolerability of donepezil and rivastigmine in DLB vs AD in everyday practice in the University-based Alzheimer’s Outpatients Clinic. Methods: A retrospective, case record analysis of AD (N⫽183) and DLB (N⫽42) patients who had been prescribed with rivastigmine or donepezil was performed. The main outcome estimates included: the tolerability of the lowest dose and the lowest effective dose for both drugs, the tolerability of the highest achieved dose, the frequency and profile of side effects, causes of drug discontinuation and the number of withdrawn cases. Results: Numerically, more subjects on rivastigmine than on donepezil were included. A maximum approved dose (10 mg for donepezil and 12 mg for rivastigmine) was achieved by an equal proportion of patients on donepezil and on rivastigmine (differences not significant). The tolerability of the lowest dose and the lowest effective dose (5 mg for donepezil and 6 mg for rivastigmine) was also similar in compared groups. The side effects profiles of both drugs were comparable and equally contributed to the drop-out rate. Conclusions: Donepezil and rivastigmine are comparably tolerated and of similar clinical benefits in a “real life” population of non-selected patients with mild to moderate AD and DLB. Cholinesterase inhibitors, considered a gold standard in the treatment of AD, might constitute a therapeutical option in DLB as well. P4-341
EFFICACY AND TOLERABILITY OF SB-742457, A NOVEL 5HT6 RECEPTOR ANTAGONIST, AND DONEPEZIL IN SUBJECTS WITH MILD-TOMODERATE ALZHEIMER’S DISEASE (AD)
Gareth Maher-Edwards1, Ruth Dixon2, Jackie Hunter2, Michael Gold3, Gillian Hopton2, Jo Hunter2, Pauline Williams2, 1GlaxoSmithKline, Greenford, Essex, United Kingdom; 2GlaxoSmithKline, Harlow, Essex, United Kingdom; 3GlaxoSmithKline, Research Triangle Park, NC, USA. Contact e-mail:
[email protected] Background: SB-742457 is a novel selective and potent 5-hydroxytryptamine 6 (5HT6) receptor antagonist that enhances cognition in aged rats. Methods: In this 24-week, double-blind, randomised study (AZ3106242), 197 subjects with mild-to-moderate AD (MMSE score 12-26) received placebo (n⫽62), SB-742457 15mg/day titrated to 35 mg/day at Week 4 (n⫽68), or donepezil 5mg/day titrated to 10 mg/day at Week 4 (n⫽67). The co-primary efficacy endpoints were the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC⫹), and the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) score at Week 24 (intention-to-treat [ITT], last observation carried forward analysis). The study was not powered to show formal statistical differences between treatment and placebo. Safety and tolerability were also assessed. Results: Eighty-five percent of subjects randomised to SB-742457 or donepezil completed the study compared to 74% of placebo-treated subjects. Approximately 90% of subjects received the maximum dose of study drug. No placebo decline for CIBIC⫹ or ADAScog was observed after 24 weeks. In the ITT population, differences from placebo in Week 24 CIBIC⫹ score were -0.17 and -0.28 for SB-742457 and donepezil, respectively. In the PP population, which excluded those subjects with pre-defined deviations from the protocol, differences from placebo in Week 24 CIBIC⫹ score were -0.27 and -0.37, respectively. Treatment differences from placebo for ADAS-cog showed similar effects on cognition with SB-742457 and donepezil (-1.1 points; PP population). Greater improvements in ADAS-Cog compared to placebo were observed for both treatments in subjects with baseline MMSE ⱕ 18 (-4.5 and -4.9 for SB-742457 and donepezil, respectively; PP population). Improvements in ADAS-Cog compared to placebo were not observed for either treatment in subjects with baseline MMSE ⬎18. All treatments were well tolerated. The proportion of subjects reporting adverse events (AEs) were placebo, 29%; SB-742457, 37%; donepezil, 39%. The most commonly reported AEs were nasopharyngitis and urinary tract infection.
