- Email: [email protected]
O1-05-07 Behavioral benefits with continued donepezil treatment in Alzheimer's disease patients
Oral Session 01-05: Therapeutics - 1
$20 I
O 1 - 0 5 - 0 5 [l DONEPEZIL AND VITAMIN E AS TREATMENTS FOR MILD COGNITIVE IMPAIRMENT Ronald Petersen* 1, Michael Grundrnan 2, Ronald Thomas 3, Leon Thai 3 .
1Mayo Clinic, Rochester, MN, USA; 2Elan Pharmaceuticals, San Diego, CA, USA; 3 University of California, San Diego, San Diego, CA, USA. Contact e-mail: [email protected] Background: MCI is recognized as a transitional state between normal aging and clinical AD. The progression rate from MCI to AD is approximately 6-25% per year and any impact of interventions on this rate would have significant public health implications. Objective(s): To determine the efficacy and tolerability of donepezil and vitamin E in slowing the rate of conversion from mild cognitive impairment (MCI) to the clinical diagnosis of Alzheimer's disease (AD). Methods: The Alzheimer's Disease Cooperative Study is a consortium of AID research centers which performs multi-center clinical trials for the treatment of AD. Sixty-nine centers in the U.S. and Canada recruited 769 subjects for this randomized, double-blind, placebocontrolled trial. The subjects, diagnosed with amnestic MCI (memory complaint, objective memory impairment, preserved general cognition and activities of daily living, and not demented), were randomized to one of three treatment arms: vitamin E 2000 IU daily, donepezil HC1 10 mg dally, or placebo and followed for three years on treatment. All subjects received a multivitamin. The primary outcome measure was conversion to clinically possible or probable AD (NINCDS/ADRDA criteria). Secondary outcome measures included the Mini-Mental State Exam, the Alzheimer's Disease Assessment Scale/Cognitive subscale, the CGIC, a neuropsychology battery, the Clinical Dementia Rating scale, Global Deterioration Scale, a quality of life assessment and the Beck Informant Questionnaire. Results: The combined group of subjects had the following characteristics: age - 72 years, education - 14.7 years, 54% male and apolipoprotein E4 carriers 55%. The combined progression rate to AD for all three groups was 13% per year, while the dropout rate was 12% per year. There were 193 conversions to possible or probable AD and 2 to other dementias. Apolipoprotein E4 cartier status was a strong predictor of conversion in the combined groups and will be discussed as a marker of prediction for the individual treatment groups. The conversion rates by groups assessing the relative efficacy of the two active treatment arms relative to placebo and side effect profiles will be discussed. Conclusions: The implication of these results for the treatment of MCI and for further clinical trials will be discussed.
IO1-05-06 ] CLINICAL DATA ON ALZHEMED J
TM AFTER 12 MONTHS OF TREATMENT IN PATIENTS WITH MILD TO MODERATE ALZHEIMER'S DISEASE
Paul A. Aisen* 1, Mariam Mehran 2, Ruth Poole 3, Isabelle Lavoie 3 , Francine Gervals 2, Julie Laurin 3, Richard Briand 3 , Denis Garceau 3 .
1Georgetown University Medical Center, Washington, DC, USA; 2Neurochem International Ltd., Walchwil, Switzerland; 3Neurochem Inc., Dorval, PQ, Canada. Contact e-mail: [email protected] Background: Cholinesterase inhibitors and memantine, drugs that target neurotransmitter activity, are the only agents approved by the FDA for the treatment of AD. A growing consensus identifies A1342as the most promising therapeutic target. Objective(s): To assess the safety, pharmacokinetics and pharmacological activity of AlzhemedTM, an anti-A[3 amyloid agent, in patients with AD. Methods: This phase II was a double-blind (DB), randomized, placebo controlled study with an open-label (OL) extension. 58 patients with MMSE scores of 13-26 were randomized to receive AlzhemedTM 50, 100, 150 mg BID or placebo for 3 months. At the end of the DB period, patients were offered AlzhemedTM 150 mg BID in an OL fashion for an additional 21 months. Routine laboratory tests, vital signs, ECGs, AlzhemedTM cerebrospinal fluid (CSF) and plasma concentrations, A~42 CSF concentrations, MMSE and ADAS-cog were assessed. Results: 52 patients completed the DB period. Four patients in the AlzhemedTM group (3 due to adverse events (AEs)) and 2 patients in the placebo group discontinued prematurely. The results from the DB period showed that AlzhemedTM is safe and well tolerated at all doses tested. The most frequent drug-related adverse events (AEs) were nausea and vomiting. These AEs
were dose-related and in most cases transient. AlzhemedTM was detected in the CSF indicating its ability to cross the blood brain barrier. After 3 months of treatment, a reduction in A[342CSF concentration of up to 70% was observed in the 100 mg and 150 mg BID groups. Among the 42 patients who entered the ongoing OL phase, 12 patients discontinued and 30 have completed the first 12 months of the study. After 1 year of follow-up, the changes from baseline (mean ± SD) in the MMSE and ADAS-cog scores for mild (MMSE > 18) AD patients (n = 18) were - 0 . 7 -4- 4.6 and 1.4 4- 6.1, respectively. Overall, in the mild to moderate patients (n = 30), the changes were - 1 . 7 -4- 4.6 and 4.3 -I- 7.2, respectively. Conclusions: AlzhemedTM was found to be safe and well tolerated in AD patients. The preliminary results are consistent with a pharmacological effect of AlzhemedTM on AI342CSF concentrations and a stabilization effect on cognitive function in mild AD patients.
BENEFITS WITH CONTINUED IO1-05-071 BEHAVIORAL DONEPEZIL TREATMENT IN ALZHEIMER'S DISEASE PATIENTS P. Johannsen* 1 R. Holub 2, G. Jakab 3, S. Jakobsen 4, C.J. Kalisvaart 5 , W. Kozubski 6, A. Kurz 7 , E. Triau 8, M. Tsolaki 9 , L. Bergendorff 1° , Y. Xu 11, N. Kumar 11, S. Richardson 12 1Rigshospitalet, Copenhagen,
Denmark; 2Neurological Association of Albany PC, Albany, NY, USA; 3Uzsoki Street Hospital of Budapest Municipality, Budapest, Hungary; 4Department of Geriatrics, Sygehus Fyn, RudkCbing, Denmark; 5Medisch Centrum Alkmaar, Alkmaar, Netherlands; 6University School of Medicine, Poznan, Poland; 7Technical University of Munich, Munich, Germany; 8Neurologie Centrum Leuven, Leuven, Belgium; 9peripheral General Hospital of Thessaloniki "Papanikolaou", Thessaloniki, Greece; 1°Pfizer Denmark, Ballerup, Denmark; ll Pfizer Inc, New York, Ny USA; 12Eisai [nc, Teaneck, NJ, USA. Contact e-mail: [email protected] Background: Donepezil provides benefits across the severity spectrum of Alzheimer's disease (AD), including for behavioral symptoms, but is often discontinued in patients whose cognition declines. Objective: To examine the behavioral benefits of continued treatment in AD patients who, during initial therapy, showed uncertain benefit as assessed by cognition and global impression. Methods: The AWARE (Aricept ® WAshout and REchallenge) study enrolled patients with mild to moderate AD and included a 24-week, open-label donepezil (10 mg/day) treatment phase, a 12-week, randomized, double-blind phase (continued donepezil or placebo) for patients showing uncertain benefit, and a 12-week, single-blind donepezil treatment phase. Patients were classified as showing uncertain clinical benefit during the open-label phase if they exhibited decline or no change on the MMSE and the physician's global impression indicated a lack of sufficient certainty of clinical benefit to continue treatment. Behavior during double-blind treatment was assessed on the Neuropsychiatric Inventory (NPI). Results are reported for intent-to-treat observed cases. Results: Following open-label treatment, patients showing uncertain benefit (n = 202) were randomized to receive donepezil (n = 99) or placebo washout (n = 103). NPI scores ranged from 0-50 at baseline. Behavioral symptoms improved in patients receiving continued donepezil, compared with decline in patients receiving placebo, and this difference was significant (least-squares mean change from NPI baseline score at Week 12: donepezil, - 2 . 4 0 4- 0.98; placebo, 0.76 4- 1.03; P=0.017). Conclusions: AD patients who continued on donepezil demonstrated behavioral benefits over those who switched to placebo, reaching statistical significance at 12 weeks. Behavioral symptoms should therefore be considered an important clinical outcome measure when evaluating treatment responses in AD patients.
$20 I
O 1 - 0 5 - 0 5 [l DONEPEZIL AND VITAMIN E AS TREATMENTS FOR MILD COGNITIVE IMPAIRMENT Ronald Petersen* 1, Michael Grundrnan 2, Ronald Thomas 3, Leon Thai 3 .
1Mayo Clinic, Rochester, MN, USA; 2Elan Pharmaceuticals, San Diego, CA, USA; 3 University of California, San Diego, San Diego, CA, USA. Contact e-mail: [email protected] Background: MCI is recognized as a transitional state between normal aging and clinical AD. The progression rate from MCI to AD is approximately 6-25% per year and any impact of interventions on this rate would have significant public health implications. Objective(s): To determine the efficacy and tolerability of donepezil and vitamin E in slowing the rate of conversion from mild cognitive impairment (MCI) to the clinical diagnosis of Alzheimer's disease (AD). Methods: The Alzheimer's Disease Cooperative Study is a consortium of AID research centers which performs multi-center clinical trials for the treatment of AD. Sixty-nine centers in the U.S. and Canada recruited 769 subjects for this randomized, double-blind, placebocontrolled trial. The subjects, diagnosed with amnestic MCI (memory complaint, objective memory impairment, preserved general cognition and activities of daily living, and not demented), were randomized to one of three treatment arms: vitamin E 2000 IU daily, donepezil HC1 10 mg dally, or placebo and followed for three years on treatment. All subjects received a multivitamin. The primary outcome measure was conversion to clinically possible or probable AD (NINCDS/ADRDA criteria). Secondary outcome measures included the Mini-Mental State Exam, the Alzheimer's Disease Assessment Scale/Cognitive subscale, the CGIC, a neuropsychology battery, the Clinical Dementia Rating scale, Global Deterioration Scale, a quality of life assessment and the Beck Informant Questionnaire. Results: The combined group of subjects had the following characteristics: age - 72 years, education - 14.7 years, 54% male and apolipoprotein E4 carriers 55%. The combined progression rate to AD for all three groups was 13% per year, while the dropout rate was 12% per year. There were 193 conversions to possible or probable AD and 2 to other dementias. Apolipoprotein E4 cartier status was a strong predictor of conversion in the combined groups and will be discussed as a marker of prediction for the individual treatment groups. The conversion rates by groups assessing the relative efficacy of the two active treatment arms relative to placebo and side effect profiles will be discussed. Conclusions: The implication of these results for the treatment of MCI and for further clinical trials will be discussed.
IO1-05-06 ] CLINICAL DATA ON ALZHEMED J
TM AFTER 12 MONTHS OF TREATMENT IN PATIENTS WITH MILD TO MODERATE ALZHEIMER'S DISEASE
Paul A. Aisen* 1, Mariam Mehran 2, Ruth Poole 3, Isabelle Lavoie 3 , Francine Gervals 2, Julie Laurin 3, Richard Briand 3 , Denis Garceau 3 .
1Georgetown University Medical Center, Washington, DC, USA; 2Neurochem International Ltd., Walchwil, Switzerland; 3Neurochem Inc., Dorval, PQ, Canada. Contact e-mail: [email protected] Background: Cholinesterase inhibitors and memantine, drugs that target neurotransmitter activity, are the only agents approved by the FDA for the treatment of AD. A growing consensus identifies A1342as the most promising therapeutic target. Objective(s): To assess the safety, pharmacokinetics and pharmacological activity of AlzhemedTM, an anti-A[3 amyloid agent, in patients with AD. Methods: This phase II was a double-blind (DB), randomized, placebo controlled study with an open-label (OL) extension. 58 patients with MMSE scores of 13-26 were randomized to receive AlzhemedTM 50, 100, 150 mg BID or placebo for 3 months. At the end of the DB period, patients were offered AlzhemedTM 150 mg BID in an OL fashion for an additional 21 months. Routine laboratory tests, vital signs, ECGs, AlzhemedTM cerebrospinal fluid (CSF) and plasma concentrations, A~42 CSF concentrations, MMSE and ADAS-cog were assessed. Results: 52 patients completed the DB period. Four patients in the AlzhemedTM group (3 due to adverse events (AEs)) and 2 patients in the placebo group discontinued prematurely. The results from the DB period showed that AlzhemedTM is safe and well tolerated at all doses tested. The most frequent drug-related adverse events (AEs) were nausea and vomiting. These AEs
were dose-related and in most cases transient. AlzhemedTM was detected in the CSF indicating its ability to cross the blood brain barrier. After 3 months of treatment, a reduction in A[342CSF concentration of up to 70% was observed in the 100 mg and 150 mg BID groups. Among the 42 patients who entered the ongoing OL phase, 12 patients discontinued and 30 have completed the first 12 months of the study. After 1 year of follow-up, the changes from baseline (mean ± SD) in the MMSE and ADAS-cog scores for mild (MMSE > 18) AD patients (n = 18) were - 0 . 7 -4- 4.6 and 1.4 4- 6.1, respectively. Overall, in the mild to moderate patients (n = 30), the changes were - 1 . 7 -4- 4.6 and 4.3 -I- 7.2, respectively. Conclusions: AlzhemedTM was found to be safe and well tolerated in AD patients. The preliminary results are consistent with a pharmacological effect of AlzhemedTM on AI342CSF concentrations and a stabilization effect on cognitive function in mild AD patients.
BENEFITS WITH CONTINUED IO1-05-071 BEHAVIORAL DONEPEZIL TREATMENT IN ALZHEIMER'S DISEASE PATIENTS P. Johannsen* 1 R. Holub 2, G. Jakab 3, S. Jakobsen 4, C.J. Kalisvaart 5 , W. Kozubski 6, A. Kurz 7 , E. Triau 8, M. Tsolaki 9 , L. Bergendorff 1° , Y. Xu 11, N. Kumar 11, S. Richardson 12 1Rigshospitalet, Copenhagen,
Denmark; 2Neurological Association of Albany PC, Albany, NY, USA; 3Uzsoki Street Hospital of Budapest Municipality, Budapest, Hungary; 4Department of Geriatrics, Sygehus Fyn, RudkCbing, Denmark; 5Medisch Centrum Alkmaar, Alkmaar, Netherlands; 6University School of Medicine, Poznan, Poland; 7Technical University of Munich, Munich, Germany; 8Neurologie Centrum Leuven, Leuven, Belgium; 9peripheral General Hospital of Thessaloniki "Papanikolaou", Thessaloniki, Greece; 1°Pfizer Denmark, Ballerup, Denmark; ll Pfizer Inc, New York, Ny USA; 12Eisai [nc, Teaneck, NJ, USA. Contact e-mail: [email protected] Background: Donepezil provides benefits across the severity spectrum of Alzheimer's disease (AD), including for behavioral symptoms, but is often discontinued in patients whose cognition declines. Objective: To examine the behavioral benefits of continued treatment in AD patients who, during initial therapy, showed uncertain benefit as assessed by cognition and global impression. Methods: The AWARE (Aricept ® WAshout and REchallenge) study enrolled patients with mild to moderate AD and included a 24-week, open-label donepezil (10 mg/day) treatment phase, a 12-week, randomized, double-blind phase (continued donepezil or placebo) for patients showing uncertain benefit, and a 12-week, single-blind donepezil treatment phase. Patients were classified as showing uncertain clinical benefit during the open-label phase if they exhibited decline or no change on the MMSE and the physician's global impression indicated a lack of sufficient certainty of clinical benefit to continue treatment. Behavior during double-blind treatment was assessed on the Neuropsychiatric Inventory (NPI). Results are reported for intent-to-treat observed cases. Results: Following open-label treatment, patients showing uncertain benefit (n = 202) were randomized to receive donepezil (n = 99) or placebo washout (n = 103). NPI scores ranged from 0-50 at baseline. Behavioral symptoms improved in patients receiving continued donepezil, compared with decline in patients receiving placebo, and this difference was significant (least-squares mean change from NPI baseline score at Week 12: donepezil, - 2 . 4 0 4- 0.98; placebo, 0.76 4- 1.03; P=0.017). Conclusions: AD patients who continued on donepezil demonstrated behavioral benefits over those who switched to placebo, reaching statistical significance at 12 weeks. Behavioral symptoms should therefore be considered an important clinical outcome measure when evaluating treatment responses in AD patients.