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New Results from Four Alzheimer's and Dementia Clinical Trials Highlight "Developing Topics" Reports at AAIC 2012

- Phase 2b study of a new symptomatic drug -
- One-year extension trial of a medical food -
- 9-month trial of a dietary supplement -
- 18-month study of a home-based care coordination intervention -

VANCOUVER, July 18, 2012 – Results from four clinical trials reported at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) demonstrate the wide variety of approaches being pursued to improve memory, thinking, quality of life, and quality of care for the millions of people with Alzheimer's, their caregivers and family members.

The four studies were presented as "developing topics" at AAIC 2012, which often include last minute calculations and data analyses. They include:

"Ridding the world of Alzheimer's disease and other dementias is a global challenge of the utmost importance," said William Thies, PhD, Alzheimer's Association® Chief Medical and Scientific Officer. "The urgency is clear. With the aging population and the growing prevalence of Alzheimer's, caring for people with dementia will cost more than $1 trillion annually by 2050 in the U.S. alone, creating an enormous strain on the already stressed healthcare system, families, and government budgets."

"As a result, having a diversity of approaches and treatment options in the pipeline is important to drug development and to affected families. While researchers are searching for ways to alter the course and prevent Alzheimer's, we still need better treatments and care options for people who have the disease now," Thies said.

Phase 2b Results of a New Symptomatic Drug

EVP-6124 (EnVivo Pharmaceuticals) is a selective, partial, alpha-7 nicotinic agonist that, in previous testing, has demonstrated cognitive benefits in normal volunteers and in preliminary study participants with schizophrenia or Alzheimer's.

Alpha-7 nicotinic agonists amplify the effects of acetylcholine, a brain chemical that is essential for normal brain and memory function. Acetylcholine is greatly reduced in people with Alzheimer's. While other approved drugs also have this effect, alpha-7 nicotinic agonists achieve the result by a different mechanism of action.

Dana Hilt, MD, Senior Vice President of Clinical Development and Chief Medical Officer of EnVivo and colleagues at the company conducted a 6-month, double blind, placebo-controlled, Phase 2b study of three doses of EVP-6124 in 409 people with mild to moderate Alzheimer's who were either on stable Alzheimer's therapy (donepezil or rivastigmine) or on no therapy. [Placebo (n=104), 0.3 mg/d (n=104), 1 mg/d (n=101), 2 mg/d (n=100).]

Primary efficacy endpoints were two established and accepted scales for measuring memory, language, attention and other cognitive abilities (ADAS-Cog-13 and the CDR-SB). Additional pre-specified endpoints included several measures of cognition, language, mood, and ability to function independently (ADAS-Cog-11, COWAT, CFT, NPI, ADCS-ADL (23)), plus composite measures for cognition, memory, and executive function.

After 23 weeks of treatment, the researchers found that, compared to the placebo group, the 2 mg treatment group had statistically significant benefits on the ADAS-Cog-13 and CDR-SB. They also saw a significant effect on the ADAS-Cog 11, COWAT, cognition composite, memory composite, and executive function composite. They reported that EVP-6124 was safe and well tolerated with some mild to moderate gastrointestinal side effects in a minority of patients in both the 1 and 2 mg dose groups.

"In our study, EVP-6124 provided significant benefits for people with mild to moderate Alzheimer's whether they were on currently-approved therapy or not," Hilt said. "While the currently approved Alzheimer's drugs provide modest improvement in cognition and function, additional symptomatic therapies are desirable. We believe that, with further testing, EVP-6124 potentially could be used as a monotherapy or added on to other approved Alzheimer's drugs. These results support studying the drug in further Phase 3 studies."

One-year Results in Mild Alzheimer's Disease with a Medical Food Product

Souvenaid® (Nutricia/Danone) is a medical food* product that, according to the manufacturers, contains a specific nutrient combination designed to support the formation and function of brain connections known as synapses.

Synapses are where brain cells pass chemical signals to other cells, and are essential to proper brain function. Alzheimer's disease destroys synapses and disrupts both the way electrical charges travel within cells and the activity of brain chemicals known as neurotransmitters.

In the 24-week, double-blind, randomized, controlled study known as Souvenir II, 259 people with mild Alzheimer's who were not taking any Alzheimer's drugs were randomized to receive either Souvenaid 125 ml once daily or a control drink. A 24-week open label extension (OLE) study, reported at AAIC 2012, enrolled patients who completed Souvenir II. In the OLE study, which was conducted at 26 study centers in six European countries (the Netherlands, Germany, France, Belgium, Italy and Spain), all patients received Souvenaid 125 ml once daily. The primary objective was to investigate long term safety and compliance following the initial double blind study. Compliance was assessed using a daily diary and by studying (nutritional) biomarkers of compliance. The memory domain score from the Neuropsychological Test Battery (NTB), the primary endpoint of the initial study, was included as an exploratory outcome in the OLE study.

The Souvenir II study recently reported a statistically significant beneficial effect on memory (Scheltens, et al. J Alz Dis, 2012). Of the 238 patients who completed that study, 198 patients entered the OLE study; 183 completed it. The OLE study results showed that 48-week use of Souvenaid was safe and well-tolerated, with high compliance (>90%). Additionally, it indicated that:

About 25% of study participants started taking approved Alzheimer drugs during the OLE; the scientists found memory improvement to be consistent across both groups.

"Souvenir II is the second positive trial showing the potential of this nutritional intervention in the early stages of Alzheimer's, and the open label data further extends our understanding. An EU-funded trial of the concept is underway, targeting patients with prodromal Alzheimer's. We look forward with great interest to the outcome," said Philip Scheltens, MD, PhD, Professor of Cognitive Neurology and Director of the Alzheimer Center at the VU University Medical Center in Amsterdam, and principal investigator of the trial.

* A medical food is defined in section 5(b) of the Orphan Drug Act (21 U.S.C. 360ee (b) (3)) as "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation."

Citicoline Supplement Tested in Older Adults with Mild Vascular Cognitive Impairment

The IDEALE study, led by Pietro Gareri, MD, PhD, of the Ambulatory Center for Dementia, Catanzaro, Italy, is a multicenter study in six regions of Italy to assess the effectiveness and safety of citicoline in 265 people aged 65+ with mild vascular cognitive impairment.

Citicoline is a dietary supplement available in more than 70 countries. Citicoline may increase the availability of certain neurotransmitters, including acetylcholine (an important brain neurotransmitter for memory processes), norepinephrine, and dopamine; and neuronal membrane phospholipids, chiefly phosphatidylcholine, which are major constituents of cell membranes.

Participants in IDEALE included older adults with MMSE (Mini Mental State Examination) scores ≥21 or people with subjective memory complaints, no evidence of deficits on MMSE and evidence of vascular lesions on brain scans. People with probable Alzheimer's disease were excluded. The study group received 500 mg of oral citicoline twice a day. Participants underwent brain imaging scans, and testing for thyroid function, cognition/memory (MMSE), independent functioning (ADL, IADL), and mood at the beginning of the study, after three months, and after nine months.

The researchers found that, after nine months, the people taking citicoline showed a slight but not significant benefit in MMSE score (22.4 at baseline, 22.9 after nine months). Those who were not taking citicoline declined (21.5 at baseline, 19.6 at nine months). The difference between the two groups was statistically significant. No adverse events were recorded.

"This study showed that citicoline is effective and well tolerated in mild vascular cognitive impairment," Gareri said "When cognitive testing scores over nine months remain unchanged in people developing cognitive impairment, we think this may be considered a good outcome."

Care Coordination Program Improves Quality of Care and Quality of Life of People with Dementia

Previous research shows that people with Alzheimer's and other dementia disorders are at increased risk for disability, medical and mental health conditions, and placement in assisted living or nursing home settings. Similarly, their caregivers are also at increased risk for a host of medical, mental health, social and economic difficulties.

Evidence also suggests that education about and management of the disease, focused on identifying and treating symptoms and providing practical and emotional support, can provide multiple benefits for those with Alzheimer's and their loved ones by minimizing the risk of complications and improving quality of life, mood, overall health, and prolonging independence.

Quincy Miles Samus, PhD, and colleagues at the Johns Hopkins University School of Medicine tested the efficacy of a multidimensional care coordination model to improve quality of care and other outcomes for community residing people with memory disorders, known as The Maximizing Independence at Home (MIND at Home) trial.

The 18-month controlled trial included 303 people with cognitive disorders (265 with dementia; 38 with mild cognitive impairment) age 70+, living at home in 28 zip codes near Baltimore, MD. Participants were randomized to receive the care coordination intervention (n=110) or augmented usual care (n=193). The intervention team included paraprofessionals specially trained in evidence-based dementia care, a psychiatric nurse, and a geriatric psychiatrist. The team implemented a standardized care coordination protocol consisting of a multidimensional needs assessment, community resource referrals, memory disorder education, counseling, and problem-solving, which were supported by a customized web-based application to monitor care progress.

Primary outcomes included unmet needs and time to transfer out of the home. Secondary outcomes were participant quality of life, neuropsychiatric symptoms, and depression.

The researchers found that study participants had a wide range of unmet needs. Home and personal safety issues, general medical care, meaningful activities, and legal issues were the most common. The intervention group had a greater decrease in total unmet needs from the beginning of the study to 18 months compared to the control group, with the most significant reductions in safety and legal issues. In addition, intervention participants were less likely to permanently leave their home or die compared to controls (30.0% vs. 45.6%) and had a significant reduction in time to leaving the home for any reason. Self-reported quality of life was better in the intervention group at 18 months. No group differences were found on proxy-rated quality of life, neuropsychiatric symptoms, or depression.

"Our study provides promising preliminary evidence that the intervention can promote the ability to age in place and improve care quality," Samus said. "We are hopeful this study will help guide how community-based dementia care can be effectively and efficiently delivered in the future."

"Further work is needed to evaluate how beneficial this intervention would be in other communities, such as those who live in disadvantaged areas. Plus, we need to work out how it might be paid for, sustained, and made available to larger groups of people over the long term," Samus said.

Recently, the Alzheimer's Association launched a new online assessment program, Alzheimer's Navigator™ (www.alzheimersnavigator.org), to help caregivers and people with dementia evaluate their needs, identify action steps and connect with local programs and services. Developed with feedback from people living with Alzheimer's and caregivers, Alzheimer's Navigator allows users to reassess needs and adjust care plans as the disease progresses. Users can create and manage care teams so that multiple people, including long-distance caregivers, can access and participate in the customized action plan.

Alzheimer's Association chapters nationwide facilitate more than 4,500 support groups and conduct 20,000 education programs annually. The Association provides consultation to 250,000 people in need each year through its toll-free 24/7 Helpline (1-800-272-3900). The only one of its kind, the Helpline is staffed by masters-level counselors and provides information and guidance in more than 170 languages and dialects.

About AAIC®
The Alzheimer's Association International Conference® (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association®
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer's through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.

 

AAIC 2012 Developing Topics
Proposal Number: 34239
Topic: Therapeutics/Therapeutic Strategies

EVP-6124, a selective alpha-7 partial agonist, has positive effects on cognition and clinical function in mild to moderate Alzheimer's disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study.

Dana Hilt, EnVivo Pharmaceuticals; Maria Gawryl, EnVivo Pharmaceuticals; Gerhard Koenig, EnVivo Pharmaceuticals, Inc.; Nancy Dgetluck, Envivo Pharmaceuticals; Hans J Moebius, EnVivo Pharmaceuticals
Presenting author e-mail: dhilt@envivopharm.com

Background: Symptomatic therapy for Alzheimer's disease (AD) is presently limited to AChEIs and Memantine. While these medications provide modest improvement in cognition and function, additional symptomatic therapies are desirable, even if disease modifying treatments are eventually developed. Alpha-7 nicotinic agonists may provide such a therapy. EVP-6124 is a selective, potent, partial, α-7 nicotinic agonist that has demonstrated procognitive effects in normal volunteers and in subjects with schizophrenia or AD.

Methods:  A Phase 2b study in AD patients was conducted to investigate the potential cognitive and clinical effects of EVP-6124. 409 AD patients, either on stable AChEI therapy (donepezil or rivastigmine at approved doses) or on no AChEI therapy were enrolled in a 6-month, double blind, placebo-controlled study to placebo (n=104), 0.3 mg/d (n=104), 1 mg/d (n=101), or 2 mg/d (n=100). Patients with a MMSE of 14-24, were enrolled. ADAS-Cog-13 and the CDR-SB were the two prespecified primary efficacy endpoints. Additional pre-specified endpoints included ADAS-Cog-11, COWAT, CFT, NPI, ADCS-ADL (23), and composite measures for cognition, memory, and executive function.

Results:  Analysis of the ITT population showed the 2 mg group when compared to the placebo group at 23 weeks (last efficacy measurement time point) to have significant effect on the ADAS-Cog-13 (cohen's d=0.39, p=0.0189), ADAS-Cog 11 (d=0.34, p=0.0151), CDR-SB (d=0.31, p=0.0253), COWAT (d=0.35, p=0.0135), cognition composite (p=0.0037), memory composite (p=0.0088) and executive function composite (p=0.0427). Favoring the 2 mg group vs placebo were the MMSE (d=0.21, p=0.0955), and ADCS-ADL (d=0.20, p=0.092). EVP-6124 was generally safe and well tolerated with some mild to moderate gastrointestinal side effects reported in a minority of patients in both the 1 and 2 mg dose groups.

Conclusions: These results demonstrate that EVP-6124 has statistical and clinically significant effects in mild to moderate AD patients either on AChEI therapy or on no specific procognitive therapy. Thus, EVP-6124 may provide useful benefit for such patients.

 

AAIC 2012 Developing Topics
Proposal Number: 34204
Topic: Therapeutics/Therapeutic Strategies

Safety, compliance and the effects on memory of 48-week Souvenaid use in mild Alzheimer's disease - results from the Souvenir II and open-label extension study

Philip Scheltens, VU University Medical Center; Jos Twisk, VU University Medical Center; Rafael Blesa, Hospital de la Sta Creu i St. Pau; Elio Scarpini, Ospedale Maggiore Policlinico IRCCS, University of Milan; Christine A.F. von Arnim, Department of Neurology University of Ulm; Anke Bongers, Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition; John Harrison, Metis Cognition Ltd.Dept of medicine Imperial College, UK; Sophie Swinkels, Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition; Richard Wurtman, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology; R.L. Wieggers, Nutricia Advanced Medical Nutrition, Danone Research Centre for Specialised Nutrition; Bruno Vellas, inserm UMR 1027; Patrick Kamphuis, Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition
Presenting author e-mail: p.scheltens@vumc.nl

Background: Synaptic dysfunction is a pathological process involved in the early stages of Alzheimer's disease (AD). Souvenaid®, containing the specific nutrient combination FortasynTM Connect, is designed to support synapse formation and function in AD. A proof-of-concept Souvenir I study showed that 12-week use of Souvenaid improved memory performance in drug-naÏve patients with mild AD. The Souvenir II study and the Souvenir II Open-Label Extension (OLE) study were designed to investigate these effects during 48 weeks. Souvenaid is a registered trademark of N.V. Nutricia. Fortasyn is a trademark of N.V. Nutricia.

Methods: In the 24-week double-blind randomised controlled Souvenir II study (NTR1975), 259 drug-naïve patients with mild AD (MMSE ≥20) were randomised to either Souvenaid or control drink. The 24-week OLE study (NTR2571) enrolled patients who completed the Souvenir II study.  In the OLE study, all patients received Souvenaid daily. Safety parameters included adverse events, vital signs and laboratory parameters. Compliance was assessed using a daily diary and by studying (nutritional) biomarkers of compliance. The memory domain score resulting from a Neuropsychological Test Battery, the primary endpoint of the Souvenir II study, was included as an exploratory outcome in the OLE study. Study staff and patients remained blinded to patient's initial study group allocation throughout the 48 weeks.

Results: The Souvenir II study demonstrated a significant effect on memory during 24 weeks intervention (Scheltens et al. J Nutr Health Aging 2011; 15(S1), S13). Of the238 patients (91.9%) who completed this study, 198 patients (83.2%) entered the OLE study. This extension study was completed by 183 patients (92.4%). The study showed that 48-week use of Souvenaid was safe, with a high compliance (>90%). The study additionally indicated that memory performance continued to improve in patients receiving Souvenaid up to 48 weeks.

Conclusions: The use of Souvenaid for 48 weeks was safe and well-tolerated in patients with mild AD. Following the significantly improved memory performance over 24 weeks in the double-blind randomised controlled Souvenir II study, the OLE study indicated that memory continued to improve in patients receiving Souvenaid up to 48 weeks.

 

AAIC 2012 Developing Topics
Proposal Number: 34018
Topic: Therapeutics/Therapeutic Strategies

Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study

Antonino Maria Cotroneo, ASL Turin; Salvatore Putignano, ASL Neaples; Fausto Fantò, University Hospital Orbassano Turin; Francesco Monteleone, Ospedale Nuovo Regina Margherita; Roberto Lacava, ASP Catanzaro; Alberto Castagna, ASP Catanzaro; Pietro Gareri, Ambulatory Center for Dementia - ASP Catanzaro - Italy
Presenting author e-mail: pietro.gareri@alice.it

Background: IDEALE study was an Italian open multicentric study on mild vascular cognitive impairment whose aim was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment.

Methods: This study was performed on 265 patients, 122 men and 143 women, mean age 79.9 ± 7.8 years old in six Italian regions. Inclusion criteria were age ≥ 65 years old, MMSE ≥ 21, or people with subjective memory complaints and no evidence of deficits on MMSE, evidence of vascular lesions on neuroradiology. People with probable Alzheimer's disease were excluded. Control group was composed by 84 patients, 36 men and 48 women, mean age 77.9 ± 7.01 years old. Patients included in the study performed brain CT or MRI, dosage of vitamin B12, folate, thyroid function. Functional dependence was investigated by ADL and IADL scales, mood was investigated by GDS and behavioural disorders by NPI scale. Comorbidity was assessed by CIRS. An assessment was made on baseline (T0), after 3 months (T1) and after 9 months (T2, six months after T1). The main outcomes were an improvement in MMSE, ADL and IADL in the study group compared to the controls; side effects were investigated too. The study group was treated by fasting oral citicoline 500 mg twice a day all over the time.

Results: MMSE score remained unchanged all over the time (22.4 ± 4 at T0; 22.7 ± 4 at T1; 22,9 ± 4 at T2), whereas a significant difference was found among the study and the control groups, p<0.0001 between T2 and T0). No differences were found in ADL and IADL scores in the two groups. A slight difference was found in GDS score among the study and control groups (p=0.06, ns). No adverse events were recorded all over the time.

Conclusions: This study showed that citicoline is effective and well tolerated in mild vascular cognitive impairment. In fact, it activates the biosynthesis of phospholipids in neuronal membranes, increases brain metabolism, norepinephrine and dopamine levels in the CNS and it has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended in vascular cognitive impairment.

 

AAIC 2012 Developing Topics
Proposal Number: 34009
Topic: Social, Behavioral, and Care Research and Practice

Efficacy of a multidimensional home-based care coordination intervention for elders with memory disorders: the Maximizing Independence at Home (MIND at Home) Trial

Quincy Miles Samus1, Deirdre Johnston1, Ed Hess1, Ann Morrison2, Peter Rabins1, Constantine Lyketsos1, Betty Black1
1Johns Hopkins University/Johns Hopkins School of Medicine, 2Copper Ridge Institute
Presenting author e-mail: qmiles@jhmi.edu

Background:  Most people with Alzheimer's disease and related memory disorders are cared for in the community by informal caregivers, but many are unrecognized and not assessed. Models of care that attend to identification and appropriate treatment at the community level must be a public health priority. This project tested the efficacy of a multidimensional care coordination model to improve quality of care and outcomes for community residing people with memory disorders.

Methods:  18-month controlled trial of 303 elders age 70+ with cognitive disorders (265 with dementia; 38 with mild cognitive impairment) living at home in 28 zip codes of north/northwest Baltimore, MD, randomized to receive the care coordination intervention (n=110) or augmented usual care (n=193). The intervention team included paraprofessionals specially trained in evidence-based dementia care, a psychiatric nurse, and geriatric psychiatrist. Interventionists implemented a standardized protocol consisting of a multidimensional needs assessment, community resource referrals, memory disorder education, counseling, and problem-solving and were supported by a customized web-based application to monitor care progress. Primary outcomes included unmet needs and time to transfer out of the home. Secondary outcomes were participant quality of life, neuropsychiatric symptoms, and depression. 

Results:  Participants had a wide range of unmet needs. Home and personal safety issues, general medical care, meaningful activities, and legal issues were the most common. The intervention group had a greater decrease in total percent unmet needs from baseline to 18 months relative to the control group (β = -1.51, SE 0.78, p=0.054), with the most significant reductions in safety (p=0.021)  and legal issues (p=0.015) domains (pre-specified). Intervention participants were less likely to permanently leave their home or die compared to controls (30.0% vs. 45.6%) and had a significant reduction in time to leaving the home for any reason (p=0.020). Self-reported quality of life was better in the intervention group at 18 months (p=0.027). No group differences were found on proxy-rated quality of life, neuropsychiatric symptoms, or depression.

Conclusions:  A multidimensional home-based care coordination intervention implemented by trained paraprofessionals and overseen by geriatric clinicians led to improvements in care quality, ability to remain in home, and better self-reported quality of life.


Contact:

Alzheimer's Association
Media line: 312.335.4078
E-mail: media@alz.org

 

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