Clinical trial NCT01504854: Resveratrol for Alzheimer's Disease
Official title: Phase II Study to Evaluate the Impact on Biomarkers of Resveratrol Treatment in Patients With Mild to Moderate Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease
Dementia
Brain diseases
Resveratrol
Memory problems
Mental disorders
Cognitive disorders
Lead sponsor: Alzheimer's Disease Cooperative Study (ADCS)
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2012-01-06
Enrollment: 119
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of probable AD (NINDS-ADRDA criteria).
* Age must be 50 years or older.
* Able to ingest oral medications.
* Caregiver/Study Partner who has direct contact with the participant more than 2 days per week to accompany participant to all visits.
* MMSE score between 14 and 26 (inclusive).
* Modified Hachinski score of less than or equal to 4.
* Able to abstain from ingesting large quantities of resveratrol-containing foods (including red wine). 1-2 glasses of red wine or red grape juice daily acceptable; 1 serving of red grapes daily acceptable.
* Able to abstain from ingesting herbal/natural preparations or dietary supplements containing resveratrol.

Exclusion Criteria:

* Non-AD dementia.
* Probable AD with Down syndrome.
* History of clinically significant stroke.
* Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
* Sensory impairment that would preclude the participant from participating in or cooperating with the protocol.
* Use of investigational agent within two months of Screening.
* Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality.
* Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history or skin melanoma or stable prostate cancer are not excluded).
* History of seizure within past five years.
* Pregnancy or possible pregnancy.
* Use of resveratrol containing supplements.

Primary outcomes:
measure: Number of Adverse Events
timeFrame: Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52
measure: Change From Baseline in Volumetric Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
timeFrame: Week 52
measure: Comparison of the Response to Treatment of Resveratrol Based on ApoE Genotype
timeFrame: Week 52
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: La Jolla
country: United States
facility: University of California, San Diego - Comprehensive Alzheimer's Program
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Beachwood
country: United States
facility: Case Western Reserve University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: N. Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: U of WA / VA Puget Sound Alzheimer's Disease Research Center
state: Washington
Study officials:
affiliation: Georgetown University
name: Raymond S. Turner, MD, PhD
role: STUDY_DIRECTOR
References:
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citation: Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010;19(1):11-26. doi: 10.3233/JAD-2010-1215.
citation: Stites SD, Turner RS, Gill J, Gurian A, Karlawish J, Grill JD; Alzheimer's Disease Cooperative Study. Research Attitudes Questionnaire scores predict Alzheimer's disease clinical trial dropout. Clin Trials. 2021 Apr;18(2):237-244. doi: 10.1177/1740774520982315. Epub 2021 Jan 10.
citation: Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.