Resveratrol for Alzheimer's Disease

NCT ID: NCT01504854

Last Updated: 2016-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 119 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2014-03-31

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.

Conditions

Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Resveratrol

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.

Group Type: EXPERIMENTAL

Resveratrol

Intervention Type: DRUG

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

Subjects will receive a matching placebo to be taken with or without food.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.

Interventions

Resveratrol

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).

Intervention Type: DRUG

Placebo

The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Alzheimer's Disease Cooperative Study (ADCS)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Raymond S. Turner, MD, PhD

Role: STUDY_DIRECTOR

Georgetown University

Locations

Banner Alzheimer's Institute

Phoenix, Arizona, United States

University of California, Irvine

Irvine, California, United States

University of California, San Diego - Comprehensive Alzheimer's Program

La Jolla, California, United States

University of Southern California

Los Angeles, California, United States

Yale University

New Haven, Connecticut, United States

Georgetown University

Washington D.C., District of Columbia, United States

Howard University

Washington D.C., District of Columbia, United States

Mayo Clinic, Jacksonville

Jacksonville, Florida, United States

University of South Florida

Tampa, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Kansas

Kansas City, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

Johns Hopkins University

Baltimore, Maryland, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic, Rochester

Rochester, Minnesota, United States

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, United States

New York University

New York, New York, United States

Mount Sinai School of Medicine

New York, New York, United States

Columbia University

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Case Western Reserve University

Beachwood, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

North Charleston, South Carolina, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

U of WA / VA Puget Sound Alzheimer's Disease Research Center

Seattle, Washington, United States

Countries

United States

References

Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6(6):e19881. doi: 10.1371/journal.pone.0019881. Epub 2011 Jun 16.

Reference Type: BACKGROUND

PMID: 21698226 (View on PubMed)

Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011 Aug;55(8):1129-41. doi: 10.1002/mnfr.201100143. Epub 2011 Jun 20.

Reference Type: BACKGROUND

PMID: 21688389 (View on PubMed)

Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:161-9. doi: 10.1111/j.1749-6632.2010.05853.x.

Reference Type: BACKGROUND

PMID: 21261655 (View on PubMed)

Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MKC, Kunz I, Schrauwen-Hinderling VB, Blaak E, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22. doi: 10.1016/j.cmet.2011.10.002.

Reference Type: BACKGROUND

PMID: 22055504 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20061622 (View on PubMed)

Greco GA, Rock M, Amontree M, Lanfranco MF, Korthas H, Hong SH, Turner RS, Rebeck GW, Conant K. CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice. Neurobiol Dis. 2023 Apr;179:106057. doi: 10.1016/j.nbd.2023.106057. Epub 2023 Mar 5.

Reference Type: DERIVED

PMID: 36878326 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33426901 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28086917 (View on PubMed)

Related Links

http://adcs.org

Alzheimer's Disease Cooperative Study

Other Identifiers

ADC-037-RES

Identifier Type: -

Identifier Source: org_study_id