- Email: [email protected]
O3-03-08: The association between family history of Alzheimer's disease, APOE status, and cognitive decline
T164
Oral O3-03: Disease Mechanisms: Apolipoprotein E
Methods: Three hundred and two subjects in the Religious Orders Study underwent determination of ApoE allele status, comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Cognitive function tests were Z scored and averaged to yield a global and five specific measures of cognitive function. Mediation analyses were used to examine whether separate pathways exist from the ⑀4 allele to cognitive function, adjusting for age, sex, education, and the amyloid and tangles pathway. Results: Results were consistent with previous findings showing that the ⑀4 allele works through amyloid and tangles to cause cognitive impairment. We estimated that the amyloid pathway accounted for 27% of the total association. The ⑀4 allele had a significant direct effect on tangles that accounted for 20% of the total association. The remaining 53% of the total association was accounted for by a significant direct effect from the ⑀4 allele to global cognition, suggesting other as yet unidentified pathways. Similar findings were found for episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Conclusions: Multiple biologic pathways appear to link the ⑀4 allele to cognitive function; some of which are currently unidentified. O3-03-06
RATE OF HIPPOCAMPAL ATROPHY IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI): EFFECTS OF APOE4 AND VALUE OF ADDITIONAL MRI SCANS
Norbert Schuff1, Nana Woerner1, Lauren Boreta1, Tess Kornfield1, C. R. Jack, Jr.2, Michael W. Weiner1, 1UCSF & VA Medical Center, San Francisco, CA, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Longitudinal MRI studies have documented increased hippocampal volume loss in AD and MCI. Most studies used a baseline and one follow-up scan to measure rates of hippocampal atrophy. Clinical treatment trials typically use measurements at multiple time points, but the value of additional MRI scans needs to be determined. This study evaluated serial hippocampal volumes at 3 time points (0-6-12 months) from data of the AD neuroimaging initative (ADNI). Our objective was to determine to what extent the addition of a 3rd MRI scan improves measurements of hippocampal atrophy rates. Specifically, we tested if 3 time points measurements are more sensitive than 2 time points in determining whether apolipoprotein E allele 4 (ApoE4) is a modifier of atrophy rates in AD. Methods: The study included 55 AD patients (age 75.4⫾7.9; MMSE 23.4⫾1.8) and age-matched 66 MCI (MMSE: 26.9⫾1.8) and 56 cognitive normal CN subjects (MMSE: 29⫾1), who completed 3 MRI scans (0, 6, and 12 months) at 1.5T. Hippocampal volumes were semi-automatically measured. Linear mixed effects repeated measures were used to separate out group effects from within subject variations. Results: Two serial measurements (0-12 months) yielded no significant effect of ApoE4 on atrophy rates in AD (p ⫽ 0.1). In contrast, three serial measurements (0-6-12 months) indicated that AD patients carrying Apoe4 had significantly higher rates of atrophy (-6.7% ⫾ 3.4 annual change) than non carriers (-3.9% ⫾ 3.4, p ⫽ 0.04). Furthermore, when atrophy rates in the first measurement interval (0-6 months) were used as confounds for rate estimations in the second interval (6-12 months), the estimation of atrophy rates overall markedly improved (p ⫽ 0.001). Conclusions: The findings that patients, who carry Apo E4 have higher rates of hippocampal atrophy suggests that the presence of this allele may accelerate progression of AD. A main benefit of 3 MRI scans is that measurements from the first interval can be used to boost power of rate measurements in the second interval. Taken together, these finding should be taken into consideration in longitudinal studies including clinical trials.
O3-03-07
REDUCED FUNCTIONAL CONNECTIVITY IN MIDDLE-AGED APOE-4 CARRIERS
Zhilin Wu, Chunming Xie, Wenjun Li, Piero Antuono, Jennifer Jones, Shi-Jiang Li, Medical College of Wisconsin, Milwaukee, WI, USA. Contact e-mail: [email protected] Background: Apolipoprotein E-4 (APOE-4) has been proven to be a major genetic risk for Alzheimer’s disease (AD). In APOE-4 carriers, cerebral glucose metabolic decline in the posterior cingulate cortex (PCC) was detected with positron emission tomography (PET) (1-2); and reduced hippocampus activation was found with fMRI (3). However, it is not known whether the functional connectivity between the hippocampus and the PCC is changed in the group of APOE-4 carriers in comparison to non-APOE-4 carriers. Objective: To test our hypothesis that the functional connectivity between the hippocampus and the PCC is reduced at resting-state among middle-aged APOE-4 carriers compared to non-APOE-4 carriers. Methods: A total of 28 neurologically normal 45- to 65-year-old subjects participated in this study. APOE genotype characterization results showed that 12 subjects carried APOE-4 (3 subjects had ⑀4/⑀4 genotype, 9 subjects had ⑀3/⑀4 genotype) and 16 subjects did not carry APOE-4. The two groups of APOE-4 carriers and non-APOE-4 carriers showed no significant difference in age, education level, and neuropsychological performances. All subjects received fMRI scans at a GE 3T scanner. Imaging datasets included whole-brain anatomical dataset and 6-min resting-state BOLDfMRI dataset. For each subject, functional connectivity between the hippocampus and PCC was obtained with cross-correlation of the spontaneous low-frequency fluctuations in the resting-state dataset. Group analysis was then performed using student t-test to determine the difference in the functional connectivity between the groups of APOE-4 carriers and non-APOE-4 carriers. Results: The functional connectivity between the hippocampus and PCC at resting-state in the APOE-4 carriers and non-APOE-4 carriers were -0.17 ⫾ 0.59 and 0.47 ⫾ 0.64, respectively. Compared to non-APOE-4 carriers, functional connectivity in the APOE-4 carriers was significantly lower (p⬍ 0.01). Conclusions: It is shown that the functional connectivity between the hippocampus and PCC at resting-state in the middle-aged APOE-4 carriers is significantly reduced. This result suggests that the reduction in the functional connectivity at resting-state of the APOE-4 carriers is associated with the risk of AD. References 1. Reiman EM et al, PNAS 2004;101:284-289. 2. Small GW et al, PNAS 2000;97:6037-6042. 3. Trivedi MA et al, BMC Medicine 2006;4:1-14. O3-03-08
THE ASSOCIATION BETWEEN FAMILY HISTORY OF ALZHEIMER’S DISEASE, APOE STATUS, AND COGNITIVE DECLINE
Kathleen M. Hayden1, Peter P. Zandi2, Nancy A. West3, JoAnn T. Tschanz4, Maria C. Norton4, Chris Corcoran4, John C. S. Breitner5, Kathleen A. Welsh-Bohmer1, 1Duke University Medical Center, Durham, NC, USA; 2Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 3University of Colorado, Denver, CO, USA; 4Utah State University, Logan, UT, USA; 5VA Puget Sound Health Care System & University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Prior studies have shown that APOE genotype is associated with old age cognitive decline as well as increased risk of Alzheimer’s disease (AD). It is likely that other, as yet unidentified genes are also associated with both outcomes. Family history of AD (FhxAD) may represent these genetic factors or other environmental factors that increase the risk of cognitive decline and AD. Few studies have evaluated the separate influences of family history of AD and APOE status on cognitive decline. Here, we evaluated the separate associations of FhxAD and APOE status
Oral O3-04: Drug Discovery: Clinical Trials on cognitive decline. Methods: Residents of Cache County, Utah, aged 65 or older as of January 1, 1995, were invited to participate. At baseline, 3,005 participants without dementia provided detailed family history of AD; they also completed the Modified Mini-Mental State Examination (3MS), and provided DNA for genotyping at APOE. They were then re-examined after three and eight years. We used mixed models to examine the association between baseline family history of AD, APOE status, and cognitive trajectory. Results: There was no significant difference in baseline score (0.11, p⫽0.68) or change over time (-0.10, p⫽0.12) in subjects with FhxAD but no APOE ⑀4 alleles vs. a reference group with no FhxAD and no ⑀4 alleles. Participants with one or more APOE ⑀4 alleles but no FhxAD scored lower (mean -0.69, p⫽0.003) on their baseline 3MS, but showed no significant difference in change over time (-0.05, p⫽0.36). Participants with both FhxAD and one or more APOE ⑀4 alleles did not have a statistically significant difference in baseline score (-0.42, p⫽0.18) but declined significantly faster over time (-0.24, p⫽0.001). Conclusions: Individuals with one or more APOE ⑀4 alleles and FhxAD declined significantly faster than those with no APOE ⑀4 allele and no FhxAD. Although the difference in change over time was numerically small, it is an estimate of difference per year, so that effects over several years could be clinically significant. Individuals with both risk factors may therefore be an important target group for intervention. TUESDAY, JULY 29, 2008 ORAL O3-04 DRUG DISCOVERY: CLINICAL TRIALS O3-04-01
SAFETY AND EFFICACY OF TARENFLURBIL IN SUBJECTS WITH MILD ALZHEIMER’S DISEASE: RESULTS FROM AN 18-MONTH MULTI-CENTER PHASE 3 TRIAL
Robert C. Green1, Lon S. Schneider2, Suzanne B. Hendrix3, Kenton H. Zavitz3, Edward Swabb4, 1Boston University School of Medicine, Boston, MA, USA; 2University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 3Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA; 4Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Tarenflurbil is a selective A42-lowering agent that modulates ␥-secretase activity to preferentially reduce production of A42 in vivo and in vitro. Preliminary evidence for potential benefit of tarenflurbil 800 mg bid in subjects with mild AD was recently observed in a randomized, double-blind Phase 2 trial. This multi-center Phase 3 study assessed the safety and efficacy of tarenflurbil in subjects with mild Alzheimer’s disease (AD). Methods: In this randomized, double-blind, placebo-controlled trial, individuals with mild AD (MMSE score 20-26, inclusive) were randomized (1:1) to receive tarenflurbil 800 mg bid or placebo for 18 months. Randomization was stratified according to use/non-use of acetylcholinesterase inhibitors and/or memantine. The co-primary outcome measures of efficacy were the ADAS-cog and the ADCS-ADL, with assessments conducted every 3 months. The secondary outcome was the CDR-sb, and exploratory outcomes included the NPI, Quality of Life-AD, and Caregiver Burden Inventory. Analysis was conducted by comparing the rate of change (slope) in the outcome measures between treatment and placebo arms. Adverse events were monitored throughout the study. Results: The study was originally powered for 1600 participants, and 1684 participants were randomized at 133 sites throughout the US between Feb 21, 2005 and Sep 1, 2006, of which 1653 had mild AD and are included in the primary analysis. At baseline, participants were 51.1% female, had a mean age (⫾ standard deviation, range) of 74.6 (⫾ 8.3, 53-94) and mean MMSE score of 23.3 (⫾ 2.0, 20-26). Conclusions: This Phase 3 protocol was powered to evaluate the efficacy of tarenflurbil with respect to the primary outcomes using an analytic strategy comparing rate of change. Results for primary and secondary efficacy outcomes will be presented, along with safety results including adverse events and lab parameters.
O3-04-02
T165
THE GINKGO IN EVALUATION OF MEMORY (GEM) STUDY: PRIMARY OUTCOMES IN A LONGITUDINAL DEMENTIA PREVENTION TRIAL
Steven T. DeKosky1, Jeff Williamson2, Annette Fitzpatrick3, Diane G. Ives1, Judith Saxton1, Oscar L. Lopez1, Gregory Burke2, Michelle Carlson4, Linda Fried4, Lewis Kuller1, John Robbins5, Russell Tracy6, Leslie O. Dunn1, Richard Kronmal3, Richard Nahin7, Curt Furberg2, for the GEMS Investigators, 1University of Pittsburgh, Pittsburgh, PA, USA; 2Wake Forest University, Winston-Salem, NC, USA; 3University of Washington, Seattle, WA, USA; 4Johns Hopkins University, Baltimore, MD, USA; 5University of California, Davis, CA, USA; 6University of Vermont, Burlington, VT, USA; 7National Center for Complementary and Alternative Medicine, Bethesda, MD, USA. Contact e-mail: [email protected] Background: Dementia is a major cause of disability in aging. However, there are few clinical trials testing interventions targeting primary prevention of dementia in the elderly. Ginkgo biloba (EGb761) is a plant extract with powerful antioxidant activity and possible anti-amyloid activity. We report results of the Ginkgo Evaluation of Memory Study (GEMS), a trial of the effectiveness of Ginkgo biloba in delaying the incidence of AD/all cause dementia. We wished test the effectiveness of 120 mg BID of Ginkgo biloba vs. placebo in lowering the incidence of AD/dementia in normal elderly or those with mild cognitive impairment (MCI). Secondary outcomes included effects of Ginkgo on cognitive change over time, vascular disease, functional decline, adverse events, and mortality. Methods: A randomized, double-blind, placebo-controlled clinical trial conducted at 4 academic sites in the US. A total of 3,071 subjects age 75⫹ with normal cognition or MCI were randomized to either Ginkgo or placebo after extensive medical and neuropsychological screening, including the Clinical Dementia Rating (CDR) performed with each participant’s proxy. Assessments were performed every 6 months; pre-defined change in cognitive scores/CDR led to more extensive testing and evaluation for dementia, including neuroimaging. Dementia outcome and specific dementia diagnosis were determined by consensus of an expert panel. Results: A total of 440⫹ persons developed dementia over the course of the study, extending 8 years from initial recruiting to date of last person/last visit. Mortality and subjects lost to follow-up were well below expected rates and Ginkgo was well tolerated. Conclusions: Statistical analysis of the trial results will be presented at the meeting. Dementia incidence is an assessable outcome in primary prevention trials. Substantial information from GEMS will be of benefit to designing future prevention trials assessing medication effectiveness. O3-04-03
A 240-MG ONCE-DAILY FORMULATION OF GINKGO BILOBA EXTRACT EGB 761® IS EFFECTIVE IN BOTH ALZHEIMER’S DISEASE AND VASCULAR DEMENTIA: RESULTS FROM A RANDOMIZED CONTROLLED TRIAL
Ralf Ihl1, Michael Tribanek2, Oleksandr Napryeyenko3, 1Alexian Hospital Krefeld, Krefeld, Germany; 2Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany; 3National Medical University, Kyiv, Ukraine. Contact e-mail: [email protected] Background: Secondary analyses of a randomized controlled trial were performed to investigate whether treatment effects of a once-daily formulation of Ginkgo biloba extract EGb 761® differed by type of dementia. Methods: 410 patients ⱖ 50 years of age diagnosed with mild to moderate dementia (Alzheimer’s disease or vascular dementia) with neuropsychiatric features were enrolled and treated with a once-daily formulation of 240 mg of EGb 761® or placebo for a period of 24 weeks. Patients scored below 36 on the TE4D screening test for dementia and between 9 and 23 on the cross-culturally validated SKT cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the total scores of the SKT cognitive battery and the NPI (primary
Oral O3-03: Disease Mechanisms: Apolipoprotein E
Methods: Three hundred and two subjects in the Religious Orders Study underwent determination of ApoE allele status, comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Cognitive function tests were Z scored and averaged to yield a global and five specific measures of cognitive function. Mediation analyses were used to examine whether separate pathways exist from the ⑀4 allele to cognitive function, adjusting for age, sex, education, and the amyloid and tangles pathway. Results: Results were consistent with previous findings showing that the ⑀4 allele works through amyloid and tangles to cause cognitive impairment. We estimated that the amyloid pathway accounted for 27% of the total association. The ⑀4 allele had a significant direct effect on tangles that accounted for 20% of the total association. The remaining 53% of the total association was accounted for by a significant direct effect from the ⑀4 allele to global cognition, suggesting other as yet unidentified pathways. Similar findings were found for episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Conclusions: Multiple biologic pathways appear to link the ⑀4 allele to cognitive function; some of which are currently unidentified. O3-03-06
RATE OF HIPPOCAMPAL ATROPHY IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI): EFFECTS OF APOE4 AND VALUE OF ADDITIONAL MRI SCANS
Norbert Schuff1, Nana Woerner1, Lauren Boreta1, Tess Kornfield1, C. R. Jack, Jr.2, Michael W. Weiner1, 1UCSF & VA Medical Center, San Francisco, CA, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Longitudinal MRI studies have documented increased hippocampal volume loss in AD and MCI. Most studies used a baseline and one follow-up scan to measure rates of hippocampal atrophy. Clinical treatment trials typically use measurements at multiple time points, but the value of additional MRI scans needs to be determined. This study evaluated serial hippocampal volumes at 3 time points (0-6-12 months) from data of the AD neuroimaging initative (ADNI). Our objective was to determine to what extent the addition of a 3rd MRI scan improves measurements of hippocampal atrophy rates. Specifically, we tested if 3 time points measurements are more sensitive than 2 time points in determining whether apolipoprotein E allele 4 (ApoE4) is a modifier of atrophy rates in AD. Methods: The study included 55 AD patients (age 75.4⫾7.9; MMSE 23.4⫾1.8) and age-matched 66 MCI (MMSE: 26.9⫾1.8) and 56 cognitive normal CN subjects (MMSE: 29⫾1), who completed 3 MRI scans (0, 6, and 12 months) at 1.5T. Hippocampal volumes were semi-automatically measured. Linear mixed effects repeated measures were used to separate out group effects from within subject variations. Results: Two serial measurements (0-12 months) yielded no significant effect of ApoE4 on atrophy rates in AD (p ⫽ 0.1). In contrast, three serial measurements (0-6-12 months) indicated that AD patients carrying Apoe4 had significantly higher rates of atrophy (-6.7% ⫾ 3.4 annual change) than non carriers (-3.9% ⫾ 3.4, p ⫽ 0.04). Furthermore, when atrophy rates in the first measurement interval (0-6 months) were used as confounds for rate estimations in the second interval (6-12 months), the estimation of atrophy rates overall markedly improved (p ⫽ 0.001). Conclusions: The findings that patients, who carry Apo E4 have higher rates of hippocampal atrophy suggests that the presence of this allele may accelerate progression of AD. A main benefit of 3 MRI scans is that measurements from the first interval can be used to boost power of rate measurements in the second interval. Taken together, these finding should be taken into consideration in longitudinal studies including clinical trials.
O3-03-07
REDUCED FUNCTIONAL CONNECTIVITY IN MIDDLE-AGED APOE-4 CARRIERS
Zhilin Wu, Chunming Xie, Wenjun Li, Piero Antuono, Jennifer Jones, Shi-Jiang Li, Medical College of Wisconsin, Milwaukee, WI, USA. Contact e-mail: [email protected] Background: Apolipoprotein E-4 (APOE-4) has been proven to be a major genetic risk for Alzheimer’s disease (AD). In APOE-4 carriers, cerebral glucose metabolic decline in the posterior cingulate cortex (PCC) was detected with positron emission tomography (PET) (1-2); and reduced hippocampus activation was found with fMRI (3). However, it is not known whether the functional connectivity between the hippocampus and the PCC is changed in the group of APOE-4 carriers in comparison to non-APOE-4 carriers. Objective: To test our hypothesis that the functional connectivity between the hippocampus and the PCC is reduced at resting-state among middle-aged APOE-4 carriers compared to non-APOE-4 carriers. Methods: A total of 28 neurologically normal 45- to 65-year-old subjects participated in this study. APOE genotype characterization results showed that 12 subjects carried APOE-4 (3 subjects had ⑀4/⑀4 genotype, 9 subjects had ⑀3/⑀4 genotype) and 16 subjects did not carry APOE-4. The two groups of APOE-4 carriers and non-APOE-4 carriers showed no significant difference in age, education level, and neuropsychological performances. All subjects received fMRI scans at a GE 3T scanner. Imaging datasets included whole-brain anatomical dataset and 6-min resting-state BOLDfMRI dataset. For each subject, functional connectivity between the hippocampus and PCC was obtained with cross-correlation of the spontaneous low-frequency fluctuations in the resting-state dataset. Group analysis was then performed using student t-test to determine the difference in the functional connectivity between the groups of APOE-4 carriers and non-APOE-4 carriers. Results: The functional connectivity between the hippocampus and PCC at resting-state in the APOE-4 carriers and non-APOE-4 carriers were -0.17 ⫾ 0.59 and 0.47 ⫾ 0.64, respectively. Compared to non-APOE-4 carriers, functional connectivity in the APOE-4 carriers was significantly lower (p⬍ 0.01). Conclusions: It is shown that the functional connectivity between the hippocampus and PCC at resting-state in the middle-aged APOE-4 carriers is significantly reduced. This result suggests that the reduction in the functional connectivity at resting-state of the APOE-4 carriers is associated with the risk of AD. References 1. Reiman EM et al, PNAS 2004;101:284-289. 2. Small GW et al, PNAS 2000;97:6037-6042. 3. Trivedi MA et al, BMC Medicine 2006;4:1-14. O3-03-08
THE ASSOCIATION BETWEEN FAMILY HISTORY OF ALZHEIMER’S DISEASE, APOE STATUS, AND COGNITIVE DECLINE
Kathleen M. Hayden1, Peter P. Zandi2, Nancy A. West3, JoAnn T. Tschanz4, Maria C. Norton4, Chris Corcoran4, John C. S. Breitner5, Kathleen A. Welsh-Bohmer1, 1Duke University Medical Center, Durham, NC, USA; 2Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 3University of Colorado, Denver, CO, USA; 4Utah State University, Logan, UT, USA; 5VA Puget Sound Health Care System & University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Prior studies have shown that APOE genotype is associated with old age cognitive decline as well as increased risk of Alzheimer’s disease (AD). It is likely that other, as yet unidentified genes are also associated with both outcomes. Family history of AD (FhxAD) may represent these genetic factors or other environmental factors that increase the risk of cognitive decline and AD. Few studies have evaluated the separate influences of family history of AD and APOE status on cognitive decline. Here, we evaluated the separate associations of FhxAD and APOE status
Oral O3-04: Drug Discovery: Clinical Trials on cognitive decline. Methods: Residents of Cache County, Utah, aged 65 or older as of January 1, 1995, were invited to participate. At baseline, 3,005 participants without dementia provided detailed family history of AD; they also completed the Modified Mini-Mental State Examination (3MS), and provided DNA for genotyping at APOE. They were then re-examined after three and eight years. We used mixed models to examine the association between baseline family history of AD, APOE status, and cognitive trajectory. Results: There was no significant difference in baseline score (0.11, p⫽0.68) or change over time (-0.10, p⫽0.12) in subjects with FhxAD but no APOE ⑀4 alleles vs. a reference group with no FhxAD and no ⑀4 alleles. Participants with one or more APOE ⑀4 alleles but no FhxAD scored lower (mean -0.69, p⫽0.003) on their baseline 3MS, but showed no significant difference in change over time (-0.05, p⫽0.36). Participants with both FhxAD and one or more APOE ⑀4 alleles did not have a statistically significant difference in baseline score (-0.42, p⫽0.18) but declined significantly faster over time (-0.24, p⫽0.001). Conclusions: Individuals with one or more APOE ⑀4 alleles and FhxAD declined significantly faster than those with no APOE ⑀4 allele and no FhxAD. Although the difference in change over time was numerically small, it is an estimate of difference per year, so that effects over several years could be clinically significant. Individuals with both risk factors may therefore be an important target group for intervention. TUESDAY, JULY 29, 2008 ORAL O3-04 DRUG DISCOVERY: CLINICAL TRIALS O3-04-01
SAFETY AND EFFICACY OF TARENFLURBIL IN SUBJECTS WITH MILD ALZHEIMER’S DISEASE: RESULTS FROM AN 18-MONTH MULTI-CENTER PHASE 3 TRIAL
Robert C. Green1, Lon S. Schneider2, Suzanne B. Hendrix3, Kenton H. Zavitz3, Edward Swabb4, 1Boston University School of Medicine, Boston, MA, USA; 2University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 3Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA; 4Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Tarenflurbil is a selective A42-lowering agent that modulates ␥-secretase activity to preferentially reduce production of A42 in vivo and in vitro. Preliminary evidence for potential benefit of tarenflurbil 800 mg bid in subjects with mild AD was recently observed in a randomized, double-blind Phase 2 trial. This multi-center Phase 3 study assessed the safety and efficacy of tarenflurbil in subjects with mild Alzheimer’s disease (AD). Methods: In this randomized, double-blind, placebo-controlled trial, individuals with mild AD (MMSE score 20-26, inclusive) were randomized (1:1) to receive tarenflurbil 800 mg bid or placebo for 18 months. Randomization was stratified according to use/non-use of acetylcholinesterase inhibitors and/or memantine. The co-primary outcome measures of efficacy were the ADAS-cog and the ADCS-ADL, with assessments conducted every 3 months. The secondary outcome was the CDR-sb, and exploratory outcomes included the NPI, Quality of Life-AD, and Caregiver Burden Inventory. Analysis was conducted by comparing the rate of change (slope) in the outcome measures between treatment and placebo arms. Adverse events were monitored throughout the study. Results: The study was originally powered for 1600 participants, and 1684 participants were randomized at 133 sites throughout the US between Feb 21, 2005 and Sep 1, 2006, of which 1653 had mild AD and are included in the primary analysis. At baseline, participants were 51.1% female, had a mean age (⫾ standard deviation, range) of 74.6 (⫾ 8.3, 53-94) and mean MMSE score of 23.3 (⫾ 2.0, 20-26). Conclusions: This Phase 3 protocol was powered to evaluate the efficacy of tarenflurbil with respect to the primary outcomes using an analytic strategy comparing rate of change. Results for primary and secondary efficacy outcomes will be presented, along with safety results including adverse events and lab parameters.
O3-04-02
T165
THE GINKGO IN EVALUATION OF MEMORY (GEM) STUDY: PRIMARY OUTCOMES IN A LONGITUDINAL DEMENTIA PREVENTION TRIAL
Steven T. DeKosky1, Jeff Williamson2, Annette Fitzpatrick3, Diane G. Ives1, Judith Saxton1, Oscar L. Lopez1, Gregory Burke2, Michelle Carlson4, Linda Fried4, Lewis Kuller1, John Robbins5, Russell Tracy6, Leslie O. Dunn1, Richard Kronmal3, Richard Nahin7, Curt Furberg2, for the GEMS Investigators, 1University of Pittsburgh, Pittsburgh, PA, USA; 2Wake Forest University, Winston-Salem, NC, USA; 3University of Washington, Seattle, WA, USA; 4Johns Hopkins University, Baltimore, MD, USA; 5University of California, Davis, CA, USA; 6University of Vermont, Burlington, VT, USA; 7National Center for Complementary and Alternative Medicine, Bethesda, MD, USA. Contact e-mail: [email protected] Background: Dementia is a major cause of disability in aging. However, there are few clinical trials testing interventions targeting primary prevention of dementia in the elderly. Ginkgo biloba (EGb761) is a plant extract with powerful antioxidant activity and possible anti-amyloid activity. We report results of the Ginkgo Evaluation of Memory Study (GEMS), a trial of the effectiveness of Ginkgo biloba in delaying the incidence of AD/all cause dementia. We wished test the effectiveness of 120 mg BID of Ginkgo biloba vs. placebo in lowering the incidence of AD/dementia in normal elderly or those with mild cognitive impairment (MCI). Secondary outcomes included effects of Ginkgo on cognitive change over time, vascular disease, functional decline, adverse events, and mortality. Methods: A randomized, double-blind, placebo-controlled clinical trial conducted at 4 academic sites in the US. A total of 3,071 subjects age 75⫹ with normal cognition or MCI were randomized to either Ginkgo or placebo after extensive medical and neuropsychological screening, including the Clinical Dementia Rating (CDR) performed with each participant’s proxy. Assessments were performed every 6 months; pre-defined change in cognitive scores/CDR led to more extensive testing and evaluation for dementia, including neuroimaging. Dementia outcome and specific dementia diagnosis were determined by consensus of an expert panel. Results: A total of 440⫹ persons developed dementia over the course of the study, extending 8 years from initial recruiting to date of last person/last visit. Mortality and subjects lost to follow-up were well below expected rates and Ginkgo was well tolerated. Conclusions: Statistical analysis of the trial results will be presented at the meeting. Dementia incidence is an assessable outcome in primary prevention trials. Substantial information from GEMS will be of benefit to designing future prevention trials assessing medication effectiveness. O3-04-03
A 240-MG ONCE-DAILY FORMULATION OF GINKGO BILOBA EXTRACT EGB 761® IS EFFECTIVE IN BOTH ALZHEIMER’S DISEASE AND VASCULAR DEMENTIA: RESULTS FROM A RANDOMIZED CONTROLLED TRIAL
Ralf Ihl1, Michael Tribanek2, Oleksandr Napryeyenko3, 1Alexian Hospital Krefeld, Krefeld, Germany; 2Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany; 3National Medical University, Kyiv, Ukraine. Contact e-mail: [email protected] Background: Secondary analyses of a randomized controlled trial were performed to investigate whether treatment effects of a once-daily formulation of Ginkgo biloba extract EGb 761® differed by type of dementia. Methods: 410 patients ⱖ 50 years of age diagnosed with mild to moderate dementia (Alzheimer’s disease or vascular dementia) with neuropsychiatric features were enrolled and treated with a once-daily formulation of 240 mg of EGb 761® or placebo for a period of 24 weeks. Patients scored below 36 on the TE4D screening test for dementia and between 9 and 23 on the cross-culturally validated SKT cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the total scores of the SKT cognitive battery and the NPI (primary