Resveratrol for Alzheimer's Disease
Resveratrol is derived from plants and is found in highest levels in red wine and the skin of red grapes. A recent study reported that monthly and weekly consumption of red wine is associated with a lower risk of dementia. There is compelling evidence that caloric restriction can improve overall health by activating a class of enzymes known as Sirtuins. Resveratrol is a substance found in some plants that directly activates sirtuins, mimicking the effects of caloric restriction and may affect regulatory pathways of diseases of aging, including Alzheimer's disease (AD).
In this study, people with AD will be given either Resveratrol or placebo for 12 months to determine whether daily resveratrol therapy is beneficial in delaying or altering the deterioration of memory and daily functioning. Subjects age 50 and above with a diagnosis of probable AD may qualify for participation in this study. A small group of 15 participants will be asked to take part in a more detailed 24-hour Pharmacokinetic (PK) sub-study that will measure resveratrol levels over a 24 hour period.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Phase II Study to Evaluate the Impact on Biomarkers of Resveratrol Treatment in Patients With Mild to Moderate Alzheimer's Disease|
- Rate of change over time on putative biomarkers of AD, particularly CSF total tau, CSF Abeta42, CSF Abeta40, and CSF phospho-tau181 [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
- Inter-arm differences in the assessment of the safety and tolerability of treatment with resveratrol [ Time Frame: Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52 ] [ Designated as safety issue: Yes ]The safety and tolerability of treatment with resveratrol will be assessed by analysis of adverse events, including symptoms, abnormal findings on physical examinations, standard laboratory tests and PK analysis of resveratrol and its major metabolites. The frequencies of adverse events or laboratory abnormalities between the participants who receive resveratrol and those receiving placebo will be compared.
- Change from baseline in volumetric magnetic resonance imaging (MRI) [ Time Frame: Screening, Weeks 13 and 52 ] [ Designated as safety issue: No ]MRI will be used to assess the effect of treatment on rate of whole brain and hippocampal atrophy as well as regional cortical thinning.
- Change in Mini-Mental State Examination (MMSE) [ Time Frame: Screening, Baseline, Weeks 6, 13, 19, 26, 32, 39, 45 and 52 ] [ Designated as safety issue: No ]The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, and comprehension. A lower score indicates more cognitive impairment. The highest score is 30.
- Change in Alzheimer's Disease Assessment Scale-Cognitive (ADAScog) [ Time Frame: Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52 ] [ Designated as safety issue: No ]The ADAScog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment and the maximum severity score is 70. A positive change indicates cognitive worsening.
- Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) [ Time Frame: Baseline, Weeks 26 and 52 ] [ Designated as safety issue: No ]The ADCS-ADL is an activities of daily living inventory developed by the ADCS to assess functional performance in participants with AD. The ADCS-ADL includes some items from traditional basic ADL tests (e.g., grooming, dressing, walking, bathing, feeding, toileting) as well as instrumental (complex) activities of daily living (e.g., shopping, preparing meals, using household appliances, keeping appointments, reading). This structured questionnaire is administered to the subject's caregiver/study partner.
- Change in Clinical Dementia Rating Scale (CDR-SOB) [ Time Frame: Baseline, Weeks 26 and 52 ] [ Designated as safety issue: No ]The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). The score is based on interviews with the participant and study partner, using a structured interview that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
- Change in Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline, Weeks 26 and 52 ] [ Designated as safety issue: No ]The NPI quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner.
- Comparison of the response to treatment of resveratrol based on ApoE genotype [ Time Frame: Baseline ] [ Designated as safety issue: No ]
- Changes in cognition, mood, and AD CSF and imaging biomarkers associated with changes in insulin and glucose metabolism [ Time Frame: Screening and Week 52 ] [ Designated as safety issue: No ]The metabolic indices will be measured and derived from oral glucose tolerance testing prior to and following resveratrol treatment, and relate them to observed changes in cognition, mood, and putative AD biomarkers.
|Study Start Date:||May 2012|
|Estimated Study Completion Date:||September 2015|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food.
The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).
Placebo Comparator: Placebo
60 subjects will receive a matching placebo to be taken with or without food.
The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
This double blind, placebo-controlled trial will be conducted at approximately 26 Alzheimer's Disease Cooperative Study (ADCS) clinical centers. One hundred twenty (120) patients with mild to moderate dementia due to probable Alzheimer's disease (AD) will be randomly assigned to treatment (1:1) with resveratrol starting at 500 mg once daily or matching placebo, increasing at 13 week intervals to a maximum of 1 gram twice daily (divided into two 500 mg capsules taken orally) taken with or without food. Participants will be treated for 52 weeks, and will undergo venous blood draws for biomarker analysis at Baseline and at 52 weeks; participants will also undergo two lumbar punctures for biomarker analyses of cerebrospinal fluid (CSF) at Baseline and at Week 52. Participants will undergo magnetic resonance imaging (MRI) to measure rate of whole-brain and regional atrophy at Screening, Week 13 and Week 52 visits. Randomization will be stratified by site. For monitoring of potential toxicities of the study drug - particularly nephrotoxicity - subjects will undergo physical examination, neurological examination, adverse event review, blood chemistries to include blood urea nitrogen (BUN) and Creatinine (Cr), pharmacokinetic (PK) analyses for resveratrol and its metabolites, and urinalysis every 6-7 weeks during the study. Clinical, Cognitive and Functional effects of resveratrol and insulin and glucose metabolism will also be assessed.
A subgroup of approximately 15 subjects enrolled will be randomized 4:1 (N = 15, 12 treated + 3 placebo) for more detailed 24-hour PK analysis. For these individuals, blood samples will be collected at 15 different time points. Measurements will include levels of resveratrol and its major metabolites (sulfated- and glucuronidated-resveratrol). These subjects will complete the detailed PK with each dosage step. This 24-hour PK sampling in the subgroup will occur after the first dose following Baseline, after the first dose at each dose increment (Weeks 13, 26 and 39), and after the final dose (Week 52).
Enrollment will be restricted to individuals who are able to abstain from ingesting large quantities of resveratrol-containing foods (including red wine). 1-2 glasses of red wine or red grape juice and 1 serving of red grapes daily is acceptable. Subjects must also be able to abstain from ingesting herbal/natural preparations or dietary supplements containing resveratrol.