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QUESTIONS ABOUT RESEARCH The search for potential wonder drugs follows a stringent path. Clinical trials proceed according to strict rules designed to protect participants. Before the US Food and Drug Administration (FDA) will authorize a clinical trial, a drug's sponsor must submit pre-clinical data from animal or test-tube studies that provide convincing preliminary evidence of safety and effectiveness. For drugs that successfully meet pre-clinical requirements, clinical testing in human subjects proceeds in three phases. Treatment must perform well enough in each phase to justify progression to the next. What are the phases of a drug trial?  Phase I trials focus on safety. Researchers enroll a small group of 20 to 80 people to determine a safe dosage range, identify side effects and learn more about how the body processes a drug. Phase II trials, which generally enroll a few hundred people, focus on demonstrating a drug's effectiveness and further evaluating its safety. Phase III trials enroll several thousand people to confirm a drug's effectiveness, compare it to existing treatments and collect more information about safety and common side effects. If a drug performs well in all phases then the developer submits to the FDA a new drug application. After reviewing the submission, the FDA grants or denies approval. It usually takes more than 10 years to move from drug discovery to FDA approval. What are the benefits and drawbacks of participation in a clinical trial? Clinical trials offer participants significant benefits, including access to treatments not yet available to the public and expert medical care at leading health centers during the trial. On the other hand, investigational treatments may cause unforeseen side effects and the treatment may turn out to be ineffective or may not work for everyone. Also, some participants will get no treatment at all; instead, as members of a control group, they will receive a placebo or sugar pill. Thus, the start of any treatment is delayed for the time of the trial. What questions should be asked before enrolling in a clinical trial?
Where do I find information on clinical trials available for participation?
How do you evaluate research findings? It is important to evaluate the results of research being done on Alzheimer's disease and related disorders. At an ever-increasing rate, the media is publicizing the results of studies done, and it can be difficult to determine how to assess the merits of studies. The Family Caregiver Alliance (an organization that supports and assists caregivers of brain-impaired adults through education, research, services and advocacy) has published a Fact Sheet on Evaluating Research Findings on Brain-Impairing Conditions. It can be accessed on their website at: www.caregiver.org/factsheets. Among the things to consider are who paid for the study to be done and whether the sponsor might have an interest in the outcome. A study financed by the latex industry that concludes that everyone should routinely wear latex gloves to minimize exposure to germs would merit skepticism.
What are the FDA-Approved Cholinesterase Inhibitors? What prescription medications are available for the treatment of Alzheimer's disease? As of February 2001, there were four prescription medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Tacrine (Cognex) was approved in 1993, donepezil (Aricept) was approved in 1996, rivastigmine (Exelon) was approved in 2000, and galantamine (Razadyne) was approved in 2001. These medications are in a class of drugs know as cholinesterase inhibitors. Because of side effects associated with tacrine, including possible liver damage, it is very rarely prescribed. What is a cholinesterase inhibitor designed to do? Cholinesterase inhibitors are designed to enhance memory and other cognitive functions by influencing certain chemical activities in the brain. Acetylcholine is a chemical messenger in the brain that scientists believe is important for the function of brain cells involved in memory, thought and judgment. Acetylcholine is released by one brain cell to transmit a message to another. Once a message is received, various enzymes, including one called acetylcholinesterase, break down the chemical messenger for reuse. In the Alzheimer-afflicted brain, the cells that use acetylcholine are damaged or destroyed, resulting in lower levels of the chemical messenger. A cholinesterase inhibitor is designed to stop the activity of acetylcholinesterase, thereby slowing the breakdown of acetylcholine. By maintaining levels of acetylcholine, the drug may help compensate for the loss of functioning brain cells. Galantamine (Razadyne) also appears to stimulate the release of acetylcholine and to strengthen the way that certain receptors on message-receiving nerve cells respond to it. What effects did cholinesterase inhibitors have on the memories of persons who took it in clinical trials? Donepezil (Aricept) and rivastigmine (Exelon) were associated with better performance in memory and thinking tests in patients who were on the active medication compared with patients taking a placebo (an inactive substance). It should be stressed that the degree of improvement was modest, and more than half of the patients showed no improvement at all. Galantamine (Razadyne) also resulted in modest improvements in clinical trials. Additional research will help scientists determine how many individuals are likely to benefit from the drug. How are cholinesterase inhibitors used? Donepezil (Aricept) is a tablet and can be administered once daily. Generally, the initial dose is 5 mg a day (usually given at night). After four to six weeks, if it is well tolerated, the dose is often increased to the therapeutic goal of 10 mg a day. Rivastigmine (Exelon) is available as a capsule or as a liquid. The dosage is gradually increased to minimize side effects. Usually the medication is started at 1.5 mg daily. After two weeks the dose is increased to 1.5 mg twice a day. The therapeutic goal is to increase the dosage gradually every two weeks to reach 6 to 12 mg a day. There is a greater frequency of side effects at these higher doses; however, taking drugs with meals may be helpful in reducing the occurrence of side effects. Galantamine (Razadyne) is supplied in the form of tablets in strengths of 4, 8, and 12 milligrams. Consult your physician to discuss the recommended regimen for this drug. What are the side effects of cholinesterase inhibitors? Symptoms such as nausea, vomiting, loss of appetite and increased frequency of bowel movements might be expected with any cholinesterase inhibitor. It is strongly recommended that a physician who is comfortable and experienced in using these medications monitor patients treated with any of these compounds and that the recommended guidelines be strictly observed. There is no evidence or reason to believe that combining the drugs would be any more beneficial than taking either one alone, and it is likely that combining the drugs would result in greater side effects. Where can I get more information? For answers to your questions about Alzheimer's disease, please call the Alzheimer's Association-RI Chapter's Helpline at (800) 272-3900. This fact sheet is provided for your information only and does not represent an endorsement of tacrine (Cognex), donepezil (Aricept), rigastigmine (Exelon) or galantamine (Razadyne) by the Alzheimer's Association. 03/01 Prepared by John C. Morris, Professor of Neurology, Washington University , St. Louis , Missouri
Memantine (Namenda) is a drug approved in October 2003 by the Food and Drug Administration (FDA) for the treatment of moderate to severe Alzheimer’s disease. Memantine was first approved in Germany in 1982 for the treatment of various neurological disorders. Since 2002 it has been approved in the rest of the European Union. It is marketed in the US by Forest Laboratories, Inc. under the trade name Namenda and has been available in pharmacies since January 2004. Memantine’s action differs from the mechanism of the cholinesterase inhibitors that were previously approved in the US for treatment of Alzheimer’s symptoms. Cholinesterase inhibitors (e.g. Aricept, Exelon and Razadyne) temporarily boost levels of acetylcholine, a messenger chemical that becomes deficient in the Alzheimer’s brain. Memantine is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, the first Alzheimer drug of this type approved in the US. It appears to work by regulating the activity of glutamate, one of the brain’s specialized messenger chemicals involved in information processing, storage and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to allow a controlled amount of calcium to flow into a nerve cell, creating the chemical environment required for information storage. Excess glutamate, on the other hand, over stimulates NMDA receptors to allow too much calcium into nerve cells, leading to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors. Because of the differing modes of action between memantine and the cholinesterase inhibitors previously approved by the FDA (Aricept, Exelon and Reminyl), studies have been conducted on the use of both types of drugs in the treatment of persons with mild to moderate Alzheimer’s disease. The results have been mixed, with some studies showing benefits from the combination therapy and others showing little or no benefits. Studies are ongoing. Memantine is supplied as an oral medication in 10 mg. Tablets. Adverse effects occurring more commonly with memantine than with placebo included headache, constipation, confusion and dizziness. Information from Memantine Fact Sheet, published by Alzheimer’s Association in 2004
What research is being done in Rhode Island LOCAL RESEARCH STUDIES NEEDING PARTICIPANTS These locations in RI are conducting research studies that need participants. Throughout the year they may add new studies as well. The Alzheimer’s Association – MA chapter maintains a listing of research sites in the MA area. (1-800-548-2111 or at: www.alzmass.org) Our website includes material on research trials in general and where to find further information. NOTE: We do not recommend or endorse particular drugs or research studies. This listing is for informational purposes only. (Updated 11/06 ) BUTLER HOSPITAL (Memory and Aging Program) Study name: A study of working memory and frontal white matter in the brains of persons with mild cognitive impairment or with normal memory Description: This study involves no treatment. It consists of memory testing and a new type of MRI given on separate occasions. It examines the relationship between how people perform on tests of thinking abilities and the health of this part of the brain. Eligibility: Participants aged 55 or older who have mild memory problems or have no memory problems Contact: Steven Correia, Ph.D. at 401-455-6403 Description: This study is designed to help caregivers who may be feeling stressed, nervous or depressed; participants do not have to be diagnosed with a clinical depression. Eligibility: Participants must: be between the ages of 18 and 90; have normal memory, be able to travel to study clinic; provide at least 20 hours/week of direct care and supervision to a person with dementia. Contact: Gary Epstein-Lubow, MD at 401-455-6384 or at GEpsteinLubow@Butler.org Description: This study is designed to assess the feelings and thoughts caregivers may be experiencing through completion of a written questionnaire. Half of the participants will then be randomly selected to be part of a follow-up study. Eligibility: Participants must be caregivers of persons who have been diagnosed with a memory problem or an anxiety or depressive disorder. Contact: Gary Epstein-Lubow, M.D. or Ivan Miller, Ph.D. at 455-6384 or GEpsteinLubow@Butler.org ______________________________________________________________________________________ Study name: A study of apathy in Alzheimer’s disease (AD) Description: This 8 week study is to determine if modafinil (a drug already approved for the treatment of other conditions) will reduce the symptoms of apathy in persons with mild to moderate AD. Apathy, the most common behavioral symptom of AD, is a distinct syndrome that can be distinguished from depression; it is defined as a loss of motivation and has symptoms which may include blunted emotions, loss of interest in previously enjoyed activities, poor effort and reduced social engagement. Treatments for depression may not reduce symptoms of apathy. Eligibility: Participants must be: diagnosed with mild to moderate AD; between the ages of 60 and 90; and experiencing symptoms of apathy. Contact: Laura Frakey, Ph.D. at 401-455-6355 Study Name: A Phase III randomized, double-blind, placebo-controlled, parallel-group study to investigate the effects of rosiglitazone (extended release tablets) (RSG XR) as adjunctive therapy in mild to moderate AD patients already being treated with donepezil (Aricept). This study is called REFLECT-2. Description: This study runs for 54 weeks and is designed to test whether RSG XR safely provides clinical benefit to people with mild to moderate Alzheimer’s disease (AD) when combined with the currently approved AD medication, Aricept (donepezil). RSG XR is a new approach to AD therapy by testing whether one’s genetic makeup affects the participant’s response to the study drug. Eligibility: Participants must be 50-90 years old and diagnosed with mild to moderate AD; at least 6 months of ongoing donezepil therapy, and have a regular care partner that can accompany them to the 10 study visits. Contact: Betty Blackham RN at Butler Hospital Memory and Aging Program at 401-455-6403 or by email to bblackham@butler.org.
RHODE ISLAND HOSPITAL (Alzheimer’s Disease and Memory Disorders Center) Study name: The VALID study: A Phase III, multi-center, randomized, placebo-controlled, double-blind study of the safety and efficacy of this medication in the treatment of persons with mild to moderate Alzheimer’s disease (AD). Description: This 26 week study will test whether Valproate, an anti-convulsant drug, is effective in delaying, weakening or preventing difficult behaviors in people with mild to moderate AD and whether it has any effect on slowing the progression of AD itself. Eligibility: Participants must: be aged between 55 to 90; be diagnosed with probable AD (mild to moderate); have NOT experienced agitation or psychosis since the onset of AD; have a study partner who can attend all visits with the participant and report on participant’s activities and behavior. Contact: Esther A. Oden, B.A., CCRC at 401-444-7691 or at eoden@lifespan.org ______________________________________________________________________________________ Study name: Alzheimer’s Disease Neuroimaging Initiative ( ADNI ) is a multi-center study to examine how brain-imaging technology can be used with other tests to measure the progression of Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD). This information will aid future clinical trials by providing assessment tools to measure the effects of treatments being studied. Description: This study will test whether serial MRI, PET, other biological markers and clinical and neuropsychological assessments can be combined to measure the progression of MCI and AD. The information obtained by studying changes in the brain images and other assessments of persons with MCI, AD as well as of healthy individuals will be used to determine the best methods for measuring treatment effects in persons with MCI and AD. Those with MCI and those who are healthy will be followed for 3 years; those persons with AD will be followed for 2 years. All participants will undergo repeated scanning; blood and urine biomarkers will be collected at the time of each scan. Eligibility: Participants must: be aged between 55 and 90; women must be 2 years post-menopausal or surgically sterile; have adequate visual and hearing to allow neuropsychological testing; permitted medication must be stable for at least 4 weeks prior to screening; for persons with MCI or AD, have memory problems; have person to accompany them to all study visits. Contact: Esther A. Oden, B.A., CCRC at 401-444-7691 or at eoden@lifespan.org Study name: A study of caregivers of persons with dementia being admitted to a long-term care facility. Description: Placing a family member or significant other in a long-term care facility can be difficult for all involved. The emotional stress of caregiving and placement can affect caregivers’ physical and mental health. The goal of the study is to understand how caregivers of persons with Alzheimer’s disease (AD) or other memory disorders adjust when placing them in a long-term care facility and to identify methods for helping these caregivers. Participants will be enrolled for 6 months to conduct assessments about their experiences with caregiving and long-term care placement. In addition, some caregivers will receive telephone calls to discuss their experiences. Eligibility: Participants must: have a family member or significant other being admitted to a long-term care facility (on a permanent basis and within a month of starting the study) because of problems related to AD or related disorder; plan to remain in the local area and be involved with them for 6 months following their placement; have their family member or significant other be at least 50 years old. Contact: Jennifer Davis, PhD or Lauren Tellier at 444-4500 or 444-0368 or at jdavis3@lifespan.org Study name: Spinal cord injury, Parkinson’s disease and Alzheimer’s disease Description: This study investigates new markers for the early detection of Alzheimer’s disease (AD) by combining fMRI (a non-invasive method to measure brain activity) with sensitive tests of attention and memory. By examining both the structural and functional changes that occur in the brain with normal aging and with AD, the study will be able to develop a better understanding of the nature of the deficits associated with the disease which should then lead to more effective rehabilitative and therapeutic treatments. Eligibility: Participants must be: aged between 60 and 85 years; healthy with no history of neurological or psychiatric impairments or diagnosed with either Mild Cognitive Impairment (MCI) or AD Contact person: Elena Festa Martino, Ph.D. at 401-863-3347 or at memorylab@brown.edu Study name: Behavioral & electrophysiological investigation of semantic memory in Alzheimer’s disease Description: This study is investigating new markers for the early detection of Alzheimer’s disease (AD) by combining EEG (a non-invasive method to measure brain activity) with sensitive tests of attention and memory. By examining the changes in cognitive functioning that occur in normal aging and in AD, the study will be able to develop a better understanding of the nature of the deficits associated with the disease which should then lead to more effective rehabilitative and therapeutic approaches. Eligibility: Participants must: be aged between 60 and 85 years; have no history of neurological or psychiatric impairments; be healthy adults or diagnosed with Mild Cognitive Impairment (MCI) or AD. Contact person: Elena Festa Marino at 401-863-3347 or at memorylab@brown.edu Study name: This is a Phase III randomized, double blind, placebo-controlled trial of the effects of Docsahexanoic acid (DHA) in slowing the progression of Alzheimer’s disease (AD) Description: This 18-month study is to determine whether DHA slows the progression of cognitive and functional decline in persons with mild to moderate AD. Eligibility: Participants must be diagnosed with mild to moderate AD and be aged 50 or older. Continued treatment with cholinesterase inhibitors (Aricept®, Exelon®, Razadyne®) or with Namenda® is allowed. Contact: Teresa Erbozkurt at 401-444-6922 or at terbozkurt@lifespan.org Study name: A study of the use of telephone screening to identify persons with Mild Cognitive Impairment Description: The purpose of this study is to develop a cost effective screening method to identify persons with Mild Cognitive Impairment (MCI) or very early Alzheimer’s disease (AD) through the use of tests/questions administered over the telephone. Eligibility: Participants need to be aged 60 to 79 years old and have either no memory loss, mild memory loss or mild AD. Contact: Megan Smith at 401-444-4500 or at MSmith23@lifespan.org RHODE ISLAND MOOD & MEMORY RESEARCH INSTITUTE Study Name: A Phase III randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of Namenda® in persons with moderate-to-severe Alzheimer's disease (AD) Description: This is a 26-week study to evaluate Namenda® when used with a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®) for persons with moderate to severe AD. Eligibility: Participants must be at least 50 years old; diagnosed with moderate to severe stage of AD; accompanied by a reliable caregiver who can provide information for the study; currently on a 3 month stable dose of a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®). Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com ______________________________________________________________________________________
Study Name: A Phase III randomized, double-blind , placebo-controlled, parallel-group study to investigate the effects of rosiglitazone (extended release tablets) as adjunctive therapy to acetylcholinesterase inhibitors (Aricept®, Exelon® or Razadyne®) on cognition and overall clinical response in APOE ε4-stratified persons with mild to moderate Alzheimer’s disease (AD) This study is called REFLECT-3. Description: This study runs for 54 weeks and is designed to test an extended release tablet for the treatment of persons with mild to moderate AD who may or may not be taking a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®). Eligibility: Participants must be at least 50 years old and diagnosed with mild to moderate AD; if on a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®) they must be on a 2 month stable dose. They must be accompanied by a reliable caregiver who has daily interaction with the study participant. Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com ______________________________________________________________________________________ Study Name: A Phase III multinational, randomized, double blind, placebo controlled study of the effect of daily treatment with MPC-7869 (Flurizan™) on measures of cognition, activities of daily living and general mental performance in persons with mild Alzheimer’s disease (AD) Description: This study runs for 18 months and is designed to determine the effectiveness of this investigational medication in the treatment of individuals with mild AD. Eligibility: Participants must be at least 55 years old, diagnosed with mild AD; may be on Namenda® with a 3-month stable dose or on an cholinesterase inhibitor (Aricept®, Exelon®, or Razadyne®) with a 6-month stable dose, accompanied by a reliable caregiver with at least 4 days per week interaction with the participant Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com ______________________________________________________________________________________
Study Name: A prospective, multi-center, single arm pilot study to evaluate the safety and tolerability of Exelon® Capsule with add on Namenda® HCI in persons with probable Alzheimer’s disease (AD). (Mini-Mental Status Exam score must be between 10-20 points.) Description: This study runs for 26 weeks and is designed to determine the effectiveness/safety of Exelon® and Namenda® as treatment for persons with AD. This is an open label study. Eligibility: Participants must be: at least 50 years old, diagnosed with probable AD, receiving a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®) for less than 6 months, and accompanied by a caregiver with at least 3 full days of interaction with the participant and daily phone contact. Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com
Study Name: A Phase II double-blind, placebo-controlled study of the activity of AVE1625 at doses of 10 mg and 40 mg for 12 weeks in persons with mild to moderate Alzheimer's disease (AD). Description: This is an 18 to 24 week safety study for persons diagnosed with mild to moderate AD. Eligibility: Participants must be: at least 50 years of age, on stable dose of a cholinesterase inhibitor (Aricept®, Exelon® or Reminyl®) for at least 3 months and accompanied by a caregiver with at least daily interaction with the participant. Participant cannot be taking Namenda®. Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com
Study Name: A Phase III randomized, double-blind, placebo-controlled, multi-center study of the safety, tolerability and efficacy of 3 doses of Lecozotan (SRA-333) SR in persons with mild to moderate Alzheimer’s disease (AD) with donepezil (Aricept®) as active control Description: This is a 3-month trial for participants diagnosed with mild to moderate AD with a follow-up open label component. Eligibility: Participants must be: at least 50 years of age, currently not taking Namenda® or a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®) and accompanied by a caregiver who has at least daily visits with the participant. Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com ______________________________________________________________________________________ Study Name: A Phase III randomized, double-blind, placebo-controlled multicenter, study of the safety, tolerability and efficacy of 3 Doses of Lecozotan (SRA-333) SR in persons with mild to moderate Alzheimer’s disease (AD) treated with a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®). Description: This is a 6 month trial for persons who are diagnosed with mild to moderate AD with a follow-up open label component. Eligibility: Participants must be: at least 50 years of age: on a 3-month stable dose of a cholinesterase inhibitor (Aricept®, Exelon® or Razadyne®); and accompanied by a caregiver who has at least daily visits with the participant. Contact: RIMMRI at 401-435-8950 or by e-mail to mmello@rimmri.com
What about a brain autopsy and tissue donation? Post-mortem examination or autopsy of the brain plays a vital role in our understanding of the diseases which cause dementia. While necessary to confirm a diagnosis of Alzheimer’s disease, a brain autopsy also provides researchers with the tissue essential to their search for a cause and cure for this disease and for more effective diagnosis and treatment. The report, which the family receives, will explain the final diagnosis and any major changes found in the brain. It will say whether or not the diagnosis of Alzheimer’s disease was confirmed and if there were any other conditions affecting the brain. If a brain autopsy is desired, it is necessary that the plans and paperwork be done well before the person’s death. Everyone associated with the person (family, primary physician, long-term care facility) needs to know that an autopsy is desired and the arrangements are in place. Then, once death has occurred, plans can proceed smoothly and efficiently. The cost of the autopsy may include pathology fees for staff and facilities to perform the autopsy and in some cases transportation of the tissue. A successful brain autopsy requires that the patient’s body be refrigerated within six hours of death. A pathologist or a pathologist’s assistant then has up to 72 hours to collect the brain tissue. Once the brain tissue is prepared for autopsy, it may be examined at any time. The brain autopsy itself is most effectively done by a specially trained neuropathologist who examines small samples of the prepared brain tissue. The brain autopsy procedure does not disfigure the body or delay the funeral. The brain tissue is removed through an incision in the back of the head. The face is never touched or scarred during the procedure. An open casket is still an option. The examination will not delay the preparation of the body for burial. In Rhode Island, the closest place which performs brain autopsies is located at RI Hospital.The Brain Tissue Resource Center (a collaborative program at RI Hospital & The Brown Medical School) conducts it's research there. For information and enrollment forms contact the director of the Brain Tissue Resource Center, Ed Stopa, M.D. at 401-444-5155. NOTE: Physicians often record causes other than Alzheimer’s disease (such a pneumonia or some other condition) as the “cause of death” on the Death Certificate. By requesting that Alzheimer’s be listed as the underlying cause of death, you can help the Board of Health maintain more accurate records regarding the true scope of this disease.
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